Conditions: Huntington Disease
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 15
Healthy volunteers: no

Brief summary:
This is a double-blind, placebo-controlled 2-period 10-week treatment within-subject crossover study of neflamapimod in early-stage Huntington disease (HD). The primary objective is to determine whether neflamapimod can reverse hippocampal dysfunction in patients with early-stage HD, as assessed by the virtual water-maze-test for evaluating spatial learning and selected tests on the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Detailed description:
The study was designed as within-subject crossover study. However, due to the Covid19 lockdowns and restrictions on clinical research, and only one subject entered the second crossover period. As a result, the baseline and outcomes are reported by the actual treatment received in the subjects during what would have been the first treatment period, i.e. placebo or neflamapimod treatment.

Arms:
arm 1: neflamapimod in Treatment Period 1, placebo in Treatment Period 2

neflamapimod: 40 mg neflamapimod hard gelatin capsules, taken twice daily with food.

Placebo: hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food. arm 2: placebo in Treatment Period 1, neflamapimod in Treatment Period 2

Placebo: hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food.

neflamapimod: 40 mg neflamapimod hard gelatin capsules, taken twice daily with food.

Interventions: intervention 1: neflamapimod intervention 2: Placebo
Intervention descriptions: intervention 1: 40 mg neflamapimod capsule intervention 2: matching placebo capsule

Protocol document:
Prot_000.pdf: 
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Title  
A  D o u ble -B li n d, Place b o -C o ntr olle d  T w o -Peri o d  1 0 -Wee k  Treat me nt 
Wit hi n -S u bject Cr oss o ver St u d y Of C o g niti ve Effects Of Nefla ma pi m o d  
i n Earl y-Sta ge H u nti n gt o n Disease ( H D)  
I n vesti g ati o n al 
Pr o d uct  
Nefla ma pi m o d  
De vel o p me nt P h ase  
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J o h n J. Al a m
Pr e si d e nt a n d C E O
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Si g nat ure  
 
 
Pri nci pal I n vesti gat or  ( pri nte d na me) 
Title:  
I nstit uti o n: 
A d dress:  
Tele p h o ne n u m ber:    
Date  


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a n d St u d y Direct or:  
J o h n J. Ala m, M D 
2 1 0  Br oa d wa y, S uite 2 0 1  
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Seri o us A d verse E ve nt Re p orti n g:  
V oisi n C o ns ulti n g Life Scie nces  
E -mail:  ei psafet y @ v oisi nc o ns ulti n g.c o m  


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Title  
A D o u ble -Bli n d, Place b o -C o ntr olle d T w o -Peri o d 1 0 -Wee k Treat me nt 
Wit hi n -S u bject Cr oss o ver St u d y o f C o g niti ve Effects o f Nefla ma pi m o d in 
Earl y -Sta ge H u nti n gt o n Disease ( H D ) 
St u d y P h ase  
2 a 
St u d y ce nter:  
Si n gle ce ntre  st u d y i n t he U nite d Ki n g d o m. 
St u d y O bjecti ves  
•  
T he pri mar y o bjecti ve is t o e val uate  t he effects of a d mi nistrati o n of 
nefla ma pi m o d o n hi p p oca m pal f u ncti o n, as assesse d i n t he virt ual 
M orris Water Maze ( M W M).  
T he sec o n dar y o bjecti ves are:  
•  
T o e val uate t he ef fects of nefla ma pi m o d o n t he Ca m bri d ge 
Ne ur o ps yc h ol o gical Test A ut o mate d Batter y ( C A N T A B) paire d 
ass ociates lear ni n g tas k.  
•  
T o e val uate effects of nefla ma pi m o d o n a lar ger batter y of 
para meters i n  t he C A N T A B.  
•  
T o e val uate t olera bilit y a n d safet y of nefla ma pi m o d i n s u bjects 
wit h H D . 
St u d y E n d p oi nts  
Pri mar y  efficac y e n d p oi nts : 
•  
Late nc y d uri n g t he lear ni n g p hase of virt ual M W M ( hi d de n 
platf or m trai ni n g) d uri n g t he  nefla ma pi m o d -treatme nt peri o d 
c o m pare d to t hat d uri n g t he place b o -a d mi nistrati o n peri o d . 
Sec o n dar y  e n d p oi nts: 
•  
Perce nt  of ti me s pe nt i n t he c orrect q ua dra nt d uri n g M W M 
pr o be test  d uri n g t he nefla ma pi m o d -treat me nt peri o d c o m pare d 
t o t hat d uri n g t he place b o-a d mi nistratio n peri o d . 
•  
N u m ber of o verall err ors i n t he C A N T A B paire d ass ociates 
lear ni n g tas k d uri n g t he nefla ma pi m o d -treat me nt peri o d c o m pare d 
t o t hat d uri n g t he place b o-a d mi nistratio n peri o d . 
•  
Safet y as deter mi ne d b y t he n u m ber of relate d a d verse e ve nts a n d 
ge neral t olera bilit y  re p orte d d uri n g t he nefla ma pi m o d treat me nt 
peri o d c o m pare d t o t he place b o a d mi nistrati o n peri o d.  
I n a d diti o n, e x pl orat or y a nal yses of t he f ull set of para meters i n t he 
C A N T A B will be c o n d ucte d.  
N u m ber of S u bjects  
A t otal of 1 6 s u bjects are pla n ne d t o be e nr olle d.  


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S u bject P o p ul ati o n  
S u bjects  a ge d 3 0 t o 7 0  years  wit h  ge neticall y c o nfir me d Sta ge 1 H D a n d 
i de ntifie d c o g niti ve deficits. 
I ncl usi o n Criteri a: 
1.  
Me n a n d w o me n  a ge 3 0 t o 7 0  years,  i ncl usi ve. 
2.  
Willi n g  a n d a ble t o pr o vi de  i nf or me d c o nse nt. 
3.  
M ust  ha ve  ge neticall y c o nfir me d H D a n d i de ntifie d 
c o g niti ve deficits: 
a. Sta ge 1, as defi ne d b y U nifie d H u nti n gt o n's Disease Rati n g 
Scale  (U H D R S ) T otal F u ncti o nal Ca pacit y ( T F C) sc ore 
≥9 , a n d, 
b.  C A N T A B Paire d Ass ociate Lear ni n g T otal A dj uste d Err or 
Sc ore of > 1 6.  
4.  
N or mal or c orrecte d e ye si g ht a n d a u dit or y a bilities, 
s ufficie nt t o perf or m  all as pects of  t he c o g niti ve a n d 
f u ncti o nal assess me nts. 
5.  
N o hist or y of lear ni n g diffic ulties t hat ma y i nterfere wit h t he  
s u bject’s a bilit y t o c o m plete t he c o g niti ve tests. 
E xcl usi o n criteri a  
1.  
A  pr ofile of i m pair me nt t hat is n ot c o nsiste nt wit h H D.  
2.  
Dia g n osis of a n y ot her o n g oi n g ce ntral n er v o us syste m 
c o n diti o n ot her  t ha n H D , i ncl u di n g, b ut  n ot  li mite d t o, 
vasc ular  de me ntia,  de me ntia  wit h  Le w y  b o dies,  a n d 
Par ki ns o n’s  disease.  
3.  
S uici dalit y,  defi ne d  as acti ve s uici dal t h o u g hts wit hi n  6  m o nt hs  
bef ore  Scree ni n g  or  at Baseli ne,  defi ne d  as a ns weri n g yes  t o 
ite ms 4 or  5 o n  t he C ol u m bia -S uici de  Se verit y  Rati n g  Scale  
( C-S S R S),  or  hist or y  of  s uici de atte m pt i n pre vi o us  2 years,  or,  
i n t he I n vesti gat or’s o pi ni o n,  at seri o us ris k of  s uici de. 
4.  
O n g oi n g  maj or  a n d acti ve ps yc hiatric  dis or der, m o derate  t o 
se vere de pressi ve  s y m pt o ms, a n d or ot her  c o nc urre nt me dical  
c o n diti o n t hat, i n t he o pi ni o n  of  t he I n vesti gat or, mi g ht  
c o m pr o mise safet y a n d/ or c o m plia nce wit h  st u d y re q uire me nts. 
5.  
Dia g n osis  of  alc o h ol or  dr u g  a b use wit hi n  t he pre vi o us  2 years.  
6.  
P o orl y  c o ntr olle d cli nicall y si g nifica nt me dical  ill ness, s uc h as 
h y perte nsi o n  ( bl o o d press ure  > 1 8 0 m m H g  s yst olic or  
1 0 0  m m H g  diast olic);  m y ocar dial  i nfarcti o n wit hi n  6 m o nt hs;  
u nc o m pe nsate d  c o n gesti ve heart  fail ure or  ot her  si g nifica nt 
car di o vasc ular, p ul m o nar y,  re nal, li ver, i nfecti o us disease,  
i m m u ne dis or der,  or  meta b olic/e n d ocri ne  dis or ders  or  ot her  
disease  t hat w o ul d  precl u de  treat me nt wit h  p 3 8  mit o ge n  


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acti vate d pr otei n  ( M A P) ki nase  i n hi bit or a n d/ or assess me nt of  
dr u g  safet y a n d efficac y. 
7.  
A ne mia wit h a he m o gl o bi n ≤1 0  g/ d L, cli nicall y si g nifica nt t h yr oi d 
f u ncti o n a b n or malit y, electr ol yte a b n or malities. 
8.  
As partate  a mi n otra nsferase ( A S T) or  ala ni ne a mi n otra nsferase 
( A L T) > 1 . 5 × t he u p per  li mit of  n or mal  ( U L N), t otal bilir u bi n  
> 1. 5  × U L N,  a n d/ or I nter nati o nal N or malize d  Rati o  (I N R) > 1. 5.  
9.  
K n o w n h u ma n  i m m u n o deficie nc y vir us ; or  acti ve he patitis  B  or 
he patitis  C  vir us  i nfecti o n; e vi de nce of acti ve or late nt t u berc ul osis. 
1 0.  
S u bject  partici pate d  i n a st u d y of  a n i n vesti gati o nal dr u g  less t ha n 
3  m o nt hs  or  5 half -li ves of  a n i n vesti gati o nal dr u g,  w hic he ver  is 
l o n ger, bef ore  e nr oll me nt i n t his st u d y. 
1 1.  
Hist or y of pre vi o us ne ur os ur ger y t o t he brai n.  
1 2.  
Fe male s u bjects w h o are  pre g na nt or  breast -fee di n g. 
1 3.  
Male  s u bjects wit h  fe male part ners  of  c hil d-beari n g  p ote ntial  
w h o  are u n willi n g  or  u na ble  t o a d here t o c o ntrace pti o n 
re q uire me nts s pecifie d i n t he pr ot oc ol  (see Secti o n 5. 8 ). 
1 4.  
Fe male s u bjects w h o ha ve n ot reac he d me n o pa use or ha ve n ot 
ha d  a  h ysterect o m y  or  bilateral  o o p h orect o m y/sal pi n g o -
o o p h orect o m y  a n d  are  n ot  willi n g  or  u na ble  t o  a d here  t o 
c o ntrace pti ve  re q uir e me nts  s pecifie d  i n  t he  pr ot oc ol  (see 
Secti o n 5. 8 ). 
1 5.  
Re q uires c o nc o mita nt use of c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4 
i n hi bit ors or a nti-t u m or necr osis fact or-al p ha t hera pies d uri n g 
st u d y partici pati o n. 
1 6.  
K n o w n aller g y t o a n y i n gre die nt of t he trial me dicati o n or place b o . 
St u d y Dr u g Det ails  
Nefla ma pi m o d  4 0  m g ca ps ule or matc hi n g place b o  ca ps ule a d mi nistere d 
orall y acc or di n g t o ra n d o mize d treat me nt assi g n me nt.    
St u d y Desi g n a n d 
Met h o ds  
T his is a P hase 2 a, si n gle ce ntre, ra n d o mize d, d o u ble-bli n d, place b o - 
c o ntr olle d, 2 -peri o d wit hi n -s u bject cr oss o ver pr o of-of -pri nci ple  st u d y 
of nefla ma pi m o d 4 0 m g or matc hi n g place b o a d mi nistere d t wice dail y 
f or 1 0 w ee ks i n s u bjects wit h Sta ge 1 H D . 
F oll o wi n g  c o m pleti o n  of  i nf or me d  c o nse nt  pr oce d ures,  s u bjects  will 
e nter t he Scree ni n g p hase of t he st u d y.  
O ne scree ni n g visit is pla n ne d  wit hi n 2 1 da ys bef ore baseli ne ( Da y 1) , 
d uri n g w hic h ti me safet y scree ni n g meas ures  a n d i nitial assess me nts, 
i ncl u di n g C A N T A B will  be u n derta ke n a n d s u bject eli gi bilit y will be 
c o nfir me d. 
O nce eli gi bilit y is c o nfir me d a n d bef ore t he first d ose of st u d y dr u g, 
s u bjects  will  be  ra n d o ml y  assi g ne d  o n  a  1: 1  basis  t o  place b o  or 


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8  s u bjects will recei ve nefla ma pi m o d a n d 8 will recei ve place b o d uri n g 
t he first treat me nt peri o d).  I n vesti gat ors a n d s u bjects will be bli n de d 
t o t he treat me nt assi g n me nt. 
D osi n g  will  start  o n  Da y  1  f oll o wi n g  c o m pleti o n  of  all  b aseli ne 
pr oce d ures ,  w hic h  will  i ncl u de  virt ual M orris  Water  Maze  ( M W M ) 
a n d C A N T A B tests . 
D uri n g  t he treat me nt peri o d,  s u bjects will  ret ur n t o t he cli nic e ver y 2 t o 
4 wee ks . 
At W ee ks 4 a n d 1 0 of t he first treat me nt peri o d, t he virt ual M W M a n d 
C A N T A B tests will be re peate d . 
All s u bjects will ret ur n f or a safet y visit 2 wee ks after st o p pi n g dr u g i n t he 
first treat me nt peri o d.   
After at least 8 wee ks (a n d u p t o 1 2 wee ks) after c o m pleti o n of t he first 
treat me nt peri o d, s u bjects will ret ur n t o t he cli nic a n d after re peati n g 
virt ual  M W M  a n d  C A N T A B,  will  res u me  bli n de d  treat me nt;  all 
s u bjects  w h o  recei ve d  place b o ca ps ules  d uri n g  t he  first  treat me nt 
peri o d  will  recei ve  nefla ma pi m o d,  w hile  t h ose  w h o  recei ve d 
nefla ma pi m o d  will  recei ve  place b o  ca ps ules  d uri n g  t his  sec o n d 
treat me nt peri o d.  
At t he en d of W ee ks 4 a n d 1 0 of t he sec o n d treat me nt peri o d, t he virt ual 
M W M a n d  C A N T A B tests will be re peate d.  
A Fi nal S t u d y V isit will be c o n d ucte d 2 wee ks after c o m pleti o n of t he 
sec o n d treat me nt peri o d. 


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T A B L E O F C O N T E N T S  
S P O N S O R P R O T O C O L A P P R O V A L P A G E  ....................................................................................... 2  
I N V E S TI G A T O R’ S SI G N AT U R E O F A G R E E M E N T P A G E  ............................................................ 3  
S P O N S O R C O N T A C T I N F O R M A TI O N  ............................................................................................... 4  
S Y N O P SI S  .................................................................................................................................................. 5  
T A B L E O F C O N T E N T S  .......................................................................................................................... 9  
LI S T O F T A B L E S  ................................................................................................................................... 1 2  
LI S T O F A B B R E VI A TI O N S  ................................................................................................................. 1 3  
1.  
I N T R O D U C TI O N ...................................................................................................................... 1 5  
1. 1.  
Scie ntific R ati o n ale  ........................................................................................................ 1 5  
1. 2.  
Pre -Cli nic al P h ar m ac ol o g y Res ults  ............................................................................. 1 6  
1. 3.  
Pri or Cli nic al E x perie nce  .............................................................................................. 1 7  
2.  
O B J E C TI V E S  ............................................................................................................................. 1 8  
2. 1.  
Pri m ar y O bjecti ve  ......................................................................................................... 1 8  
2. 2.  
Sec o n d ar y O bjecti ves  .................................................................................................... 1 8  
3.  
I N V E S TI G A TI O N A L P L A N .................................................................................................... 1 9  
3. 1.  
O ver all St u d y Desi g n a n d Pl a n  .................................................................................... 1 9  
3. 1. 1.  
Scree ni n g  ......................................................................................................... 1 9  
3. 1. 2.  
Treat me nt Peri o d  ............................................................................................. 1 9  
3. 1. 3.  
Earl y Disc o nti n uati o n  ..................................................................................... 1 9  
3. 2.  
Disc ussi o n of St u d y Desi g n  ........................................................................................... 2 0  
3. 2. 1.  
Rati o nale f or D ose Selecti o n  ........................................................................... 2 0  
4.  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  .............................................................................. 2 2  
4. 1.  
I ncl usi o n Criteri a ........................................................................................................... 2 2  
4. 2.  
E xcl usi o n Criteri a  .......................................................................................................... 2 2  
4. 3.  
Re m o v al of S u bjects fr o m Tre at me nt  .......................................................................... 2 3  
5.  
T R E A T M E N T S A D MI NI S T E R E D  .......................................................................................... 2 4  
5. 1.  
P ac k a gi n g a n d L a beli n g  ................................................................................................ 2 4  
5. 2.  
St u d y Dr u g S u p pl y, St or a ge, a n d H a n dli n g  ................................................................ 2 4  
5. 3.  
Dr u g Acc o u nt a bilit y, Dis p os al, Ret ur n, or Rete nti o n of U n use d St u d y 
Dr u g  ................................................................................................................................ 2 4  
5. 4.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nt Gr o u p  .................................................. 2 4  
5. 5.  
St u d y Bli n di n g a n d Bre a ki n g t he Bli n d  ....................................................................... 2 5  
5. 6.  
D ose M o dific ati o n f or T o xicit y  ..................................................................................... 2 5  


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P ri or a n d C o nc o mit a nt T her a p y  .................................................................................. 2 5  
5. 8.  
C o ntr ace pti o n a n d Pre g n a nc y  ...................................................................................... 2 7  
5. 9.  
Acti vit y Restricti o ns  ..................................................................................................... 2 8  
5. 1 0 . 
Tre at me nt C o m pli a nce  ................................................................................................. 2 8  
6.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................................................... 2 9  
6. 1.  
Sc he d ule of Assess me nts  ............................................................................................... 2 9  
6. 2.  
St u d y Assess me nts  ......................................................................................................... 3 2  
6. 2. 1.  
Baseli ne a n d Disease C haracteristics  .............................................................. 3 2  
6. 2. 2.  
C ol u m bia -S uici de Se verit y Rati n g Scale  ........................................................ 3 2  
6. 2. 3.  
H os pital A n xiet y a n d De pressi o n Scale  .......................................................... 3 2  
6. 2. 4.  
U nifie d H u nti n gt o n's Disease Rati n g Scale  .................................................... 3 2  
6. 2. 5.  
C A N T A B  ........................................................................................................ 3 3  
6. 2. 6.  
M orris Water Maze Test  ................................................................................. 3 4  
6. 2. 7.  
P h ysical E xa mi nati o n a n d Vital Si g ns  ............................................................ 3 5  
6. 2. 8.  
1 2 -Lea d Electr ocar di o gra m  ............................................................................. 3 5  
6. 2. 9.  
Cli nical La b orat or y Assess me nts  .................................................................... 3 5  
6. 2. 1 0.  
Wit h dra wal of S u bjects  ................................................................................... 3 6  
7.  
A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S/ S A F E T Y 
R E P O R TI N G  .............................................................................................................................. 3 8  
7. 1.  
Defi niti o ns a n d Criteri a  ................................................................................................ 3 8  
7. 1. 1.  
A d verse E ve nts  ............................................................................................... 3 8  
7. 1. 2.  
Seri o us A d verse E ve nts  .................................................................................. 3 8  
7. 1. 3.  
U ne x pecte d A d verse Dr u g Reacti o ns  ............................................................. 3 9  
7. 1. 4.  
A b n or mal La b orat or y Val ues  .......................................................................... 3 9  
7. 1. 5.  
Assessi n g I nte nsit y a n d Relati o ns hi p  .............................................................. 3 9  
7. 2.  
Re p orti n g Pr oce d ures a n d Re q uire me nts  ................................................................... 4 1  
7. 2. 1.  
A d verse E ve nts  ............................................................................................... 4 1  
7. 2. 2.  
Seri o us A d verse E ve nts  .................................................................................. 4 1  
8.  
D A T A M A N A G E M E N T A N D S T A TI S TI C A L A N A L Y SI S  ................................................. 4 3  
8. 1.  
D at a M a n a ge me nt a n d Q u alit y Ass ur a nce C o nsi der ati o ns  ....................................... 4 3  
8. 2.  
S a m ple Size  ..................................................................................................................... 4 3  
8. 3.  
A n al ysi s Sets ................................................................................................................... 4 3  


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8. 4.  
S afet y  .............................................................................................................................. 4 4  
8. 5.  
Effic ac y  ........................................................................................................................... 4 4  
8. 6.  
I nteri m A n al ysis ............................................................................................................. 4 4  
9.  
S T U D Y M A N A G E M E N T  ......................................................................................................... 4 5  
9. 1.  
Et h ics a n d C o nse nt ........................................................................................................ 4 5  
9. 1. 1.  
Re g ulati o ns a n d G ui deli nes  ............................................................................ 4 5  
9. 1. 2.  
I n de pe n de nt Et hics C o m mittee ....................................................................... 4 5  
9. 1. 3.  
I nf or me d C o nse nt ............................................................................................ 4 5  
9. 2.  
I n de m nific ati o n .............................................................................................................. 4 5  
9. 3.  
Disc o nti n u ati o n of t he St u d y b y t he S p o ns or  .............................................................. 4 5  
9. 4.  
St u d y D oc u me nt ati o n  .................................................................................................... 4 6  
9. 5.  
St u d y M o nit ori n g a n d A u diti n g  ................................................................................... 4 6  
9. 6.  
Use of St u d y Fi n di n gs  .................................................................................................... 4 6  
9. 7.  
P u blic ati o ns  .................................................................................................................... 4 6  
9. 8.  
Rec or di n g, Access a n d Rete nti o n of S o urce D at a  ....................................................... 4 6  
9. 9.  
Pr ot oc ol Vi ol ati o ns  ........................................................................................................ 4 7  
1 0.  
R E F E R E N C E S  ........................................................................................................................... 4 8  


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LI S T O F T A B L E S  
Ta ble 5 -1:  
C Y P 3 A 4 I n hi bit ors ( Pr o hi bite d)  ...................................................................................... 2 6  
Ta ble 5 -2:  
C Y P 3 A 4 I n d ucers (t o be Use d wit h Ca uti o n)  ................................................................. 2 7  
Ta ble  6 -1  
Sc he d ule of Assess me nts  ................................................................................................. 3 0  
Ta ble  6 -2  
Cli nical La b orat or y A nal ytes  .......................................................................................... 3 6  


 EI P 1 9 -N F D -4 0 1, Versi o n 3. 0, 3 0 J uly, 2 0 1 9 
P a ge 1 3  of 5 0  
 
EI P P h ar m a, I nc  
C o nfi de nti al  
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
A D  
Alz hei mer’s disease  
A D R  
A d verse dr u g reacti o n  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A P P  
A m yl oi d -prec urs or -pr otei n  
A S K 1  
A p o pt osis si g nal -re g ulati n g ki nase 1 
A S T  
As partate a mi n otra nsferase  
A U C  
Area u n der t he ti me c o nce ntrati o n c ur ve  
BI D  
bis i n die (t wice a da y)  
C A N T A B  
C L  
Ca m bri d ge Ne ur o ps yc h ol o gical Test A ut o mate d Batter y  
Cleara nce  
C N S  
Ce ntral Ner v o us S yste m  
C -S S R S  
C ol u m bia -S uici de  Se verit y  Rati n g  Scale  
C Y P  
C yt oc hr o me P 4 5 0  
E C G  
Electr ocar di o gra m  
eC R F  
Electr o nic Case  re p ort f or m 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G A B A A  
γ-a mi n o b ut yric aci d t y pe A  
H D  
H u nti n gt o n’s Disease  
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I N D 
I n vesti gati o nal Ne w Dr u g 
 
 
L F T  
Li ver f u ncti o n test  
M A P  
Mit o ge n -acti vate d pr otei n  
M A P 2 K 6  
p 3 8 M A P -Ki nase 6  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M K P -1  
Mit o ge n -acti vate d pr otei n ki nase p h os p hatase 1  
M O T  
M ot or Scree ni n g Tas k  


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C o nfi de nti al  
A b bre vi ati o n  
Defi niti o n  
m T O R  
Ma m malia n tar get of ra pa m yci n  
M W M  
M orris -Water -Maze  
O T S  
O ne T o uc h St oc ki n gs of Ca m bri d ge  
p 3 8 α  
M it o ge n-acti vate d pr otei n ki nase 1 4  
P A L  
Paire d Ass ociate d Lear ni n g  
P R M  
Patter n Rec o g niti o n Me m or y  
R A  
R he u mat oi d art hritis  
R TI  
Reacti o n Ti me  
S A E  
Seri o us a d verse e ve nt  
S S  
S pacial S pa n  
T F C  
T otal F u ncti o nal Ca pacit y  
U H D R S  
U nifie d H u nti n gt o n's Disease Rati n g Scale  
U L N  
U p per li mit of n or mal  


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1.  
I N T R O D U C TI O N 
1. 1.  
Scie ntific R ati o n ale  
T his is a d o u ble -bli n d, place b o -c o ntr olle d 2 -peri o d 1 0 -wee k treat me nt wit hi n -s u bject cr oss o ver st u d y of 
nefla ma pi m o d i n earl y -sta ge H u nti n gt o n disease ( H D).  T he pri mar y o bjecti ve is t o deter mi ne w het her 
nefla ma pi m o d ca n re verse hi p p oca m pal d ysf u ncti o n i n patie nts wit h earl y -sta ge H D, as assesse d b y t he 
virt ual M orris Water Maze test  ( M W M) f or e val uati n g s patial lear ni n g a n d selecte d tests o n t he 
Ca m bri d ge Ne ur o p s yc h ol o gical Test A ut o mate d Batter y ( C A N T A B).   
W hile H D is defi ne d as a m o ve me nt dis or der, c o g niti ve deficits prece de m ot or deficits a n d rece ntl y , 
i m pair me nt i n hi p p oca m p us-de pe n de nt c o g niti ve f u ncti o n was defi ne d as o ne of t he earliest ma nifestati o n 
of H D ( Be geti et al, 2 0 1 6 ).  T hese res ults of Be geti et al c o nfir m pri or st u dies i n m ulti ple a ni mal m o dels 
t hat de m o nstrate d d ysre g ulati o n of hi p p oca m pal s y na ptic d ysf u ncti o n (Mil ner w o o d & Ra y m o n d, 2 0 1 0 ; 
S mit h et al, 2 0 1 4 ; Giralt et al, 2 0 1 2 ).  F urt her s y na ptic d ysf u ncti o n a n d ne ur o de ge nerati o n has bee n, i n 
tra ns ge nic m o dels directl y li n ke d t o t he t o xicit y of m uta nt h u nti n gti n (H T T ) s y na pses (X u et al, 2 0 1 3 ; 
Vale ncia et al, 2 0 1 3 ; Se pers & Ra y m o n d, 2 0 1 4 ).  Fr o m a mec ha nistic sta n d p oi nt, t he s y na ptic t o xicit y 
a p pears t o be a res ult of defects i n pr otei n traffic ki n g/ de gra dati o n as c orrecti o n t hr o u g h i ncreasi n g 
e n d os o mal t raffic ki n g via o vere x pressi o n of Ra b 1 1 (Stei nert et al, 2 0 1 1 ), w hile i ncreasi n g a ut o p ha g y b y 
i ncreasi n g ma m malia n tar get of ra pa m yci n ( m T O R ) acti vit y (Lee et al, 2 0 1 5 ), re verses s y na ptic 
d ysf u ncti o n a n d a meli or ates be ha vi oral/ m ot or deficits.  I n a d diti o n, s y na ptic d ysf u ncti o n has bee n li n ke d 
t o disr u pti o n of γ-a mi n o b ut yric aci d t y pe A  (G A B A A ) rece pt or traffic ki n g (Y ue n et al, 2 0 1 2 ).   
Nefla m api m o d is a hi g hl y s pecific i n hi bit or of t he i ntr a-cell ular e nz y me mit o ge n -acti vate d pr otei n ki nase 
1 4 ( p 3 8 α) t hat is c urre ntl y bei n g e val uate d i n a p hase 2 b cli nical st u d y i n earl y Alz hei mer’s disease ( A D).  
I n t he brai n, p 3 8 α re g ulates i nfla m mati o n t hr o u g h effects o n micr o glia.  M ore o ver, u n der c o n diti o ns of 
stress a n d disease, p 3 8 α is als o e x presse d i n ne ur o ns a n d of t he vari o us p 3 8 is of or ms, t he al p ha is of or m is 
t he m ost i m p orta nt re g ulat or of t he stress res p o nse i n ne ur o ns (La ws o n et al, 2 0 1 3 ).  I n t he ne ur o n, p 3 8 α 
als o a p pears t o pla y a critical r ole i n i nfla m mati o n -dri ve n t o xicit y t o s y na pses ( Watters o n et al, 2 0 1 3 ; 
P riet o et al, 2 0 1 5).  As a res ult of t his u n dersta n di n g, p 3 8 M A P K α has bee n rec o g nize d as a lea di n g 
t hera pe utic tar get t o i m pr o ve hi p p oca m pal s y na ptic f u ncti o n a n d s y na ptic plasticit y f or a br oa d ra n ge of 
ce ntral ner v o us s yste m ( C N S ) dis or ders ( C orrêa  et al, 2 0 1 2; Sa n derse n et al, 2 0 1 6 ).  M ore rece ntl y, usi n g 
selecti ve i n hi bit ors of p 3 8 α, tw o gr o u ps ha ve de m o nstrate d t hat s h ort -ter m ( 2-3 wee ks) treat me nt re verse s 
s patial lear ni n g deficits i n t he Ra dial Ar m Water Maze a n d M orris-Water -Maze ( M W M) tests i n t he 
Alz hei mer’s A P P/ P S 1 tra ns ge nic m o use ( R o y et al, 2 0 1 5 ) a n d t he A ge d Rat (Ala m, 2 0 1 5 ) m o dels, 
res pecti vel y.  F urt her, ge netic re d ucti o n of ne ur o nal p 3 8 α i n am yl oi d -p rec urs or-p r otei n ( A P P) 
o vere x pressi n g tra ns ge nic mice i m pr o ves s y na ptic tra ns missi o n a n d plasticit y (i.e. pre ve nts s y na ptic 
d ysf u ncti o n), re d uces me m or y l oss, a n d re d uces a m yl oi d pat h ol o g y ( C o lié et al, 2 0 1 7).  Ge neticall y 
k n oc ki n g d o w n p 3 8 α i n ne ur o ns als o pr otecte d mice fr o m de vel o pi n g a ge -relate d hi p p oca m pal 
d ysf u ncti o n a n d decli ne i n ne ur o ge nesis ( C ortez et al, 2 0 1 7 ). 
I n t he H D c o nte xt, p 3 8 acti vati o n has bee n de m o nstrate d i n t he tra ns ge nic Y A C 1 2 8 m o use m o del of 
disease ( Da u et al 2 0 1 4 ; Gla d di n g et al, 2 0 1 4 ) a n d bee n i m plicate d i n vitr o i n e x pa n de d-p ol y gl uta mi ne 
me diate d c y ot o xicit y ( Ts irig otis et al, 2 0 0 8 ).  I n a d diti o n, o vere x pressi o n of m it o ge n-acti vate d pr otei n 
ki nase p h os p hatase 1  (M K P -1 ), w hic h re d uces t he acti vit y of p 3 8 a n d ot her mit o ge n -acti vate d pr otei n 
(M A P ) ki nase pat h wa ys, is ne ur o pr otecti ve i n a le nti vir us m o del of H D ( Ta yl or et al, 2 0 1 3 ).  I n h u ma ns, 
p 3 8 α has bee n i m plicate d as ge netic l oci of t w o u pstrea m acti vat ors of p 3 8 α, ap o pt osis si g nal-re g ulati n g 


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k i nase 1 (A S K 1 ) a n d p 3 8 M A P -Ki nase 6  (M A P 2 K 6 ), w hic h ha ve bee n i de ntifie d as a ge netic m o difier of 
t he a ge of o nset i n H D (Ar ni n g et al, 2 0 0 8 ). 
Re gar di n g nefla ma pi m o d i n precli nical a n d earl y p hase  st u dies, it has bee n s h o w n t o re verse s patial 
lear ni n g deficits, as assesse d i n t he M W M  test, i n a ge d rats (Ala m et al 2 0 1 5 ).  T he s patial lear ni n g 
deficits i n t he a ge d rat is c o nsi dere d t o be t he res ult of i nfla m mati o n -i n d uce d hi p p oca m pal s y na ptic 
d ysf u ncti o n.  M ore o ver, i n p hase 2a cli nical st u dies i n patie nts wit h earl y A D , nefla ma pi m o d 
de m o nstrate d me di u m t o lar ge effect size wit hi n -s u bject i m pr o ve me nt i n perf or ma nce o n tests of 
i m me diate a n d dela ye d recall (i.e. tests of e pis o dic me m or y), w hic h are k n o w n t o be de pe n de nt o n pr o per 
hi p p oca m pal f u ncti o n ( G ol d & B u ds o n, 2 0 0 8) .  T hese preli mi nar y cli nical res ults are bei n g e val uate d i n a 
2 4 -wee k place b o -c o ntr olle d st u d y i n earl y A D t hat is o n g oi n g .  Nefla ma pi m o d has n ot bee n e val uate d 
pre vi o usl y i n H D.  
1. 2.  
Pre -Cli nic al  P h ar m ac ol o g y Res ults  
T o o btai n precli nical pr o of -of -pri nci ple  f or a n effect o n hi p p oca m pal s y na ptic d ysf u ncti o n, nefla ma pi m o d 
was teste d i n t he a ge d rat m o del of a ge -relate d c o g niti ve decli ne.  W he n teste d i n a n M W M test, rats 
s h o w c o g niti ve deficits starti n g at 2 0 t o 2 2  m o nt hs of a ge .  T his deficit has bee n s h o w n t o be a res ult of 
i nfla m mati o n-i n d uce d i m paire d of s y na ptic plasticit y i n t he hi p p oca m p us ( 3 8 TKell y, 2 0 0 3
3 8 T; 3 8 TL y nc h, 2 0 1 0
3 8 T). 
T he p u blis he d res ults (
3 8Ala m, 2 0 1 5
3 8 T) s h o we d t hat nefla ma pi m o d a d mi nistere d f or 3 wee ks f ull y re verse d 
t he s patial lear ni n g deficits i n t he M W M test i n 2 0- t o 2 2-m o nt h ol d rats wit h i de ntifie d c o g niti ve deficits, 
wit h t he perf or ma nce of a ge d rats treate d wit h nefla ma pi m o d at t he o pti mal d ose bei n g si g nifica ntl y 
better t ha n ve hicle ( place b o) - treate d a ge d rats (P  =  0. 0 0 7) a n d bei n g si milar t o t hat of y o u n g rats .  T hese 
data c o m bi ne d wit h d ose -res p o nse data i n pre vi o us a ni mal a n d cli nical st u dies, were t he n utilize d t o 
i de ntif y d oses f or t he P hase 2a cli nical st u dies  i n earl y Alz hei mer’s disease.  
N efla ma pi m o d also was st u die d i n a n i n d uce d -str o ke m o del i n rats:  tra nsie nt isc he mia of s ufficie nt 
d urati o n was i n d uce d s uc h t hat si g nifica nt ne ur ol o gic disa bilit y de vel o pe d wit h o ut m ortalit y a n d t he 
ne ur ol o gic disa bilit y di d n ot s u bsta ntiall y re verse d uri n g f oll o w -u p wi t h o ut t hera p y.  T hese rats were t he n 
treate d wit h ve hicle (c o ntr ol) or nefla ma pi m o d.  Starti n g at 4 8-h o urs after str o ke,  a d mi nistrati o n of 
nefla ma pi m o d f or 6 wee ks  le d t o s u bsta ntial i m pr o ve me nt o n m ulti ple para meters of ne ur ol o gic f u ncti o n 
c o m pare d t o ve h icle c o ntr ols (P  < 0. 0 0 1 f or eac h of gl o bal ne ur ol o gic sc ores, m ot or - a n d se ns or y -s pecific 
tests).  As rec o ver y after str o ke is de pe n de nt o n ne ur o nal a n d s y na ptic plasticit y (
3 8 TC h ollet, 2 0 1 3
3 8 T), t hese 
res ults f urt her c o nfir m t hat nefla ma pi m o d is acti ve i n re versi n g i m paire d s y na ptic plasticit y i n a ni mal 
m o del s. 
Base d o n t he scie ntific rati o nale a n d e mer gi n g mec ha nistic u n dersta n di n g of t he effects of i n hi biti o n of 
ne ur o nal p 3 8 α  (refer t o Secti o n  1. 1 ), t he de m o nstrate d p ositi ve p har mac ol o gical effects of nefla ma pi m o d 
ma y be d ue t o re versi n g pr ote ostasis defects wit hi n  hi p p oca m pal  ne ur o n s, i ncl u di n g i m paire d a ut o p ha g y 
a n d e n d ol ys os o mal d ysf u ncti o n (
3 8 TAla m & Sc he per, 2 0 1 6
3 8 T).  T he pr ote ostasis  defect -re versi n g p ote ntial of 
nefla ma pi m o d was rece ntl y c o nfir me d i n a h u ma n i n vitr o s yste m ( D o w n S y n dr o me fi br o blasts), w here 
nefla ma pi m o d at c o nce ntrati o ns  bel o w 1 0  n M  re verse d e n d os o mal a b n or malities a n d i m pr o ve d l ys os o mal 
f u ncti o n (co nf i de ntial data o n file). 


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1. 3.  
Pri or Cli nic al E x perie nce  
Nefla ma pi m o d has bee n teste d n o n -cli nicall y a n d cl i nicall y i n A D a n d als o i n earlier st u dies i n 
r he u mat oi d art hritis ( R A) a n d t he ris ks t o date are well d oc u me nte d.  I n l o n g -ter m ( 9- a n d 1 2-m o nt h) 
t o xicit y st u dies i n t he d o g, pat h ol o gical e vi de nce of t o xicit y was e vi de nt i n t he li ver a n d C N S 
( pre d o mi na ntly a x o nal da ma ge i n t he s pi nal c or d).  T he fi n di n gs are disc usse d i n detail i n t he i n vesti gat or 
br oc h ure, b ut t here were o nl y mi ni mal t o e q ui v ocal fi n di n gs e vi de nt at bl o o d dr u g c o nce ntrati o ns te n -f ol d 
hi g her t ha n t h ose ac hie ve d i n h u ma ns wit h t he 4 0 m g t wi ce-dail y ( BI D) d ose t o be utilize d i n t he pla n ne d 
cli nical st u d y ( n. b: t he n o -a d verse-effect le vel was t w o -f ol d hi g her o n a plas ma dr u g c o nce ntrati o n basis).  
I n t he rece nt A D cli nical st u dies, nefla ma pi m o d was well t olerate d, wit h 2 4 of 2 5 s u bjects c o m pleti n g 
t heir sc he d ule d d osi n g peri o d.  T he o ne s u bject w h o disc o nti n ue d earl y di d s o wit hi n t he first wee k of 
st u d y dr u g a d mi nistrati o n d ue t o a n a d verse e ve nt ( A E) of v o miti n g, attri b ute d pri maril y t o persiste nt 
C S F lea ka ge after t he pre d ose/ baseli ne C S F c o llecti o n.  T here were n o se vere or seri o us A Es re p orte d .  
T he m ost c o m m o n A Es acr oss t he 2 A D st u dies were mil d s o m n ole nce re p orte d i n 5 patie nts, a n d self -
li miti n g mil d diarr h oea re p orte d i n 4 patie nts.  T here was als o o ne e ve nt of m o derate diarr h oea, w hi c h 
was c o nsi dere d n ot relate d, as t he e ve nt di d n ot rec ur d uri n g t he a d diti o nal 8 wee ks of treat me nt after 
ha vi n g res ol ve d d uri n g a brief treat me nt i nterr u pti o n .  N o treat me nt -relate d or cli nicall y rele va nt tre n ds i n 
t he a nal ysis of safet y la b orat or y a n d 12 -lea d electr ocar di o gra m ( E C G) para meters were o bser ve d.  M ore 
s pecificall y, t here were n o a b n or malities i n li ver f u ncti o n tests ( L F Ts), n or a n y tre n ds i n c ha n ges i n L F T 
para meters, n ote d i n eit her st u d y.  I ncreases i n li ver tra nsa mi nases ha ve bee n i de ntif ie d as t he d ose-
li miti n g cli nical t o xicit y i n pri or cli nical st u dies.  T his was see n i n 1 0 % t o 1 5 % of patie nts wit h R A  i n a 
pri or st u d y at a d ose of 2 5 0 m g BI D f or 3 m o nt hs; a d ose le vel at w hic h t he plas ma dr u g c o nce ntrati o ns 
were 4 - t o 5-f ol d hi g her t ha n i n t he pre vi o us or pla n ne d A D st u dies.   
T here is a n o n g oi n g d o u ble -bli n de d ra n d o mize d st u d y i n earl y A D .  T he st u d y is desi g ne d t o treat 
1 5 2  patie nts wit h eit her nefla ma pi m o d 4 0 m g or place b o BI D .  T he st u d y is o n g oi n g a n d bli n de d.  T here 
has bee n o ne re p orte d u nrelate d seri o us a d verse e ve nt (S A E ) of h y p o kale mia.  T he dr u g was i nterr u pte d 
b ut re -starte d.  T here has bee n o ne re p ort of li ver tra nsa mi nase i ncreases t o >3 ti mes t he u p per li mit of 
n or mal.  B ot h ala ni ne a mi n otra nsferase ( A L T ) a n d as partate a mi n otra nsferase ( A S T ) were i ncrease d t o 
sli g htl y > 3 ti mes t he u p per li mit of n or mal, a n d t here was n o ass ociate d i ncrease i n bilir u bi n.  T he patie nt 
ha d n o ot her i ll ness or s y m pt o ms, hist or y of m o derate alc o h ol i nta ke, a n d t he tra nsa mi nase le vels be ga n 
t o res ol ve d uri n g c o nti n ue d st u d y dr u g a d mi nistrati o n.  St u d y dr u g is c urre ntl y i nterr u pte d , a n d t he 
s u bject’s treat me nt assi g n me nt has n ot bee n u n bli n de d.  Ot her wise  i n t his st u d y t he maj orit y of e ve nts 
ha ve bee n mi l d t o m o derate a n d u nrelate d. 
Gi ve n t he p ote ntial be nefits t o patie nts wit h earl y H D, t he safet y mar gi n relati ve t o a ni mal t o xicit y 
fi n di n gs, a n d t he pri or cli nical e x perie nce at s u bsta ntiall y hi g her d ose le vels, t he be nefit/ris k pr ofile is 
fa v o ura ble f or t he pla n ne d st u d y at t he 4 0 m g BI D d ose le vel.    


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2.  
O B J E C TI V E S  
2. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve is:  
•  
T o e val uate t he effects of a d mi nistrati o n of nefla ma pi m o d  o n hi p p oca m pal f u ncti o n, as assesse d 
i n t he virt ual M W M. 
2. 2.  
Sec o n d ar y  O bjecti ves  
T he sec o n dar y o bjecti ves are:  
•  
T o e val uate t he effects of nefla ma pi m o d o n t he  C A N T A B paire d ass ociates lear ni n g tas k.  
•  
T o e val uate effects of nefla ma pi m o d o n a lar ger batter y of p ara meters i n t he C A N T A B.  
•  
T o  e val uate t olera bilit y a n d safet y of nefla ma pi m o d i n s u bjects wit h H D. 


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I N V E S TI G A TI O N A L P L A N  
3. 1.  
O ver all St u d y Desi g n a n d Pl a n  
T his is a P hase 2a, si n gle ce ntre , ra n d o mize d, d o u ble-bli n d, place b o - c o ntr olle d, t w o -peri o d wit hi n -
s u bject cr oss o ver pr o of-of -pri nci ple st u d y of nefla ma pi m o d 4 0 m g or matc hi n g place b o a d mi nistere d BI D  
f or 1 0 wee ks i n s u bjects wit h Sta ge 1 H D. 
A t least 8 wee ks (a n d u p t o 1 2 wee ks) after co m pleti o n of t he first treat me nt peri o d, s u bjects will ret ur n t o 
t he cli nic a n d after re peati n g virt ual M W M a n d C A N T A B, will res u me bli n de d treat me nt; all s u bjects 
w h o recei ve d place b o ca ps ules d uri n g t he first treat me nt peri o d will recei ve nefla ma pi m o d, w hile t h ose 
w h o recei ve d nefla ma pi m o d will recei ve place b o ca ps ules d uri n g t his sec o n d treat me nt peri o d.  
A sc he d ule of assess me nts is prese nte d i n Ta ble  6 -1 .  
3. 1. 1.  
Scree ni n g  
F oll o wi n g c o m pleti o n of i nf or me d c o nse nt pr oce d ures, s u bjects will e nter t he Scree ni n g p hase of t he 
st u d y.  O ne scree ni n g visit is pla n ne d wit hi n 2 1 da ys bef ore baseli ne ( Da y 1) , d uri n g w hic h safet y 
scree ni n g meas ures a n d assess me nts, i ncl u di n g C A N T A B , will be u n derta ke n a n d s u bject eli gi bilit y 
will be c o nfir me d . 
3. 1. 2.  
Treat me nt Peri o d  
O nce eli gi bilit y is c o nfir me d a n d bef ore t he first d ose of st u d y dr u g, s u bjects will be ra n d o ml y assi g ne d 
o n a 1: 1 basis t o place b o or nefla m a pi m o d treat me nt d uri n g t he first treat me nt peri o d (i.e., 8 s u bjects will 
recei ve nefla ma pi m o d a n d 8 will recei ve place b o d uri n g t he first treat me nt peri o d); refer t o Secti o n  5. 4  
f or details re gar di n g assi g n me nt t o treat me nt gr o u p.  I n vesti gat ors a n d s u bjects will be bli n de d t o t he 
treat me nt assi g n me nt. 
D osi n g will start o n Da y 1 f oll o wi n g c o m pleti o n of all baseli ne pr oce d ures, w hic h will i ncl u de virt ual 
M W M a n d C A N T A B tests.  
At Wee ks 4 a n d 1 0 of t he first treat me nt peri o d, t he virt ual M W M a n d C A N T A B tests will be re peate d . 
All s u bjects will ret ur n f or a safet y visit 2 wee ks after st o p pi n g dr u g i n t he first treat me nt peri o d.    
A t least 8 wee ks (a n d u p t o 1 2 wee ks) after c o m pleti o n of t he first treat me nt peri o d, s u bjects will ret ur n t o 
t he cli nic a n d after re peati n g virt ual M WM a n d C A N T A B, will res u me bli n de d treat me nt; all s u bjects w h o 
recei ve d place b o ca ps ules d uri n g t he first treat me nt peri o d will recei ve nefla ma pi m o d, w hile t h ose w h o 
recei ve d nefla ma pi m o d will recei ve place b o ca ps ules d uri n g t his sec o n d treat me nt peri o d.  
A t t he e n d of Wee ks 4 a n d 1 0 of t he sec o n d treat me nt peri o d, t he virt ual M W M a n d C A N T A B tests will be 
re peate d. 
A Fi nal St u d y Visit will be c o n d ucte d 2 wee ks after c o m pleti o n of t he sec o n d treat me nt peri o d.  
3. 1. 3.  
Earl y Disc o nti n uati o n  
S u bjects w h o pre mat urel y dis c o nti n ue st u d y dr u g f or a n y reas o n will be as ke d t o ret ur n t o t he cli nical site 
f or a n Earl y Ter mi nati o n visit wit hi n 3 da ys f oll o wi n g t he last st u d y dr u g d ose; if it is deter mi ne d t hat t he 
s u bject will disc o nti n ue st u d y dr u g w hile at t he st u d y ce nter f or a sc he d ule d visit, t he n t he Earl y 


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Ter mi nati o n visit s h o ul d be c o n d ucte d at t hat ti me.  T hese s u bjects will als o be as ke d t o ret ur n t o t he 
cli nical site f or a F oll o w-u p Visit 2 wee ks  ( ± 3 da ys ) f oll o wi n g t he last st u d y dr u g d ose .   
E ver y eff ort s h o ul d be ma d e t o e ns ure a s u bject ret ur ns f or t his visit.  
Refer t o Secti o n  4. 3  f or details re gar di n g re m o val of s u bjects fr o m treat me nt. 
3. 2.  
Disc ussi o n of St u d y Desi g n  
Gi ve n t he i nter -s u bject varia bilit y i n t he le vel of c o g niti ve d ysf u ncti o n i n H u nti n gt o n’s disease, a cr oss-
o ver desi g n, i n w hic h eac h s u bject will ser ve as his or her o w n c o ntr ol,  w o ul d pr o vi de si g nifica ntl y m ore 
statistical p o wer t o detect treat me nt differe nces t ha n a parallel gr o u p desi g n.  I n a d diti o n, gi ve n t hat a n y 
be neficial effects o f nefla ma pi m o d w o ul d  be t hr o u g h i m pr o ve me nt of s y na ptic f u ncti o n (i.e. a f u ncti o nal 
effect) a n y p ote ntial effects w o ul d be e x pecte d t o was h-o ut relati vel y ra pi dl y (i.e. wit hi n a s mall n u m ber of 
wee ks).  
As a sec o n dar y o bjecti ve, t he i m pact of nefla ma pi m o d o n sl o wi n g t he decli n e i n c o g niti ve f u ncti o n i n 
s u bjects wit h H D will be assesse d usi n g t he C A N T A B, a met h o d c o m m o n l y e m pl o ye d i n cli nical st u dies 
(S mit h  et al, 2 0 1 3).  I n partic ular, t he effect of nefla ma pi m o d o n t he C A N T A B p aire d ass ociates lear ni n g 
tas k as well as o n t he M W M test, tests k n o w n t o rel y o n hi p p oca m pal i nte grit y (Be geti, 2 0 1 6 ), will be 
assesse d. 
3. 2. 1.  
Rati o nale f or D ose Selecti o n  
3. 2. 1. 1.  
Efficac y C o nsi derati o ns  
T he 4 0 m g BI D re gi me n was c h ose n base d o n p har mac o ki netic -p har mac o d y na mic  m o deli n g ( plas ma 
dr u g c o nce ntrati o n res p o nse) c orrelati o ns, w hic h i n dicate d a plas ma dr u g c o nce ntrati o n de pe n de nc y o n 
t he effects o n e pis o dic me m or y t hat ar g ues a gai nst g oi n g t o l o wer d oses a n d o nl y m o dest f urt her i ncreases 
i n efficac y wit h utilizi n g a 1 2 5  m g d ose le vel, w hile t he l oss of a n a m yl oi d pla q ue l oa d effect at 1 2 5 m g 
d ose le vel pr o vi des a s pecific reas o n n ot t o i ncrease t he d ose a b o ve 4 0 m g .  T he p har mac o ki netic -
p har mac o d y na mic  m o deli n g was als o c o nsiste nt wit h t he i n vitr o p ote nc y  of t he dr u g a n d pre dicte d d oses 
f or o pti mal c o g niti ve effects base d o n pre-cli nical st u dies  ( 3 8 TAla m, 2 0 1 5
3 8 T).  M ore o ver, t he 4 0 m g d ose le vel 
pr o vi des a n a p pr o priate safet y mar gi n relati ve t o c hr o nic t o xic ol o g y fi n di n gs i n t he d o g . 
3. 2. 1. 2.  
Safet y C o nsi derati o ns  
Base d o n t he cli nical e x perie nce t o date at hi g her d oses a n d t he res ults fr o m a ni mal t o xic ol o g y st u dies, 
t he nefla ma pi m o d d ose of 4 0 m g BI D a n d l o wer is e x pecte d t o be well t olerate d a n d t o ha ve a l o w ris k of 
dr u g t o xicit y.  
I n t he P hase 2a st u dies ( St u d y 3 0 3) of 6- or 1 2 -wee ks nefla ma pi m o d d osi n g i n patie nts wit h mil d A D, a 
t otal of 2 5 s u bjects were e nr olle d.  Wit h re gar d t o  safet y, nefla ma pi m o d was well t olerate d, wit h 2 4 of 
2 5  s u bjects c o m pleti n g t heir sc he d ule d d osi n g peri o d ( 8 c o m plete d 6 wee ks of nefla ma pi m o d 
a d mi nistrati o n, a n d 1 6 c o m pleti n g 1 2 wee ks of nefla ma pi m o d a d mi nistrati o n) .  T he o ne s u bject w h o 
disc o nti n ue d ear l y di d s o wit hi n t he first wee k of st u d y dr u g a d mi nistrati o n d ue t o a n a d verse e ve nt ( A E) 
of v o miti n g, attri b ute d pri maril y t o persiste nt cere br os pi nal fl ui d lea ka ge after t he pre d ose/ baseli ne C S F 
c ollecti o n.  T here were n o se vere or seri o us A Es re p orte d .  T he m ost c o m m o n A Es acr oss t he 2  st u dies 
were mil d s o m n ole nce (slee pi ness or dr o wsi ness) re p orte d i n 5 patie nts, a n d self -li miti n g mil d diarr hea 
(l o ose st o ols) re p orte d i n 4 patie nts.  T here was als o o ne e ve nt of m o derate diarr hea, w hic h was 


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c o nsi dere d n o t relate d, as t he e ve nt di d n ot rec ur d uri n g a d diti o nal 8 wee ks of treat me nt after ha vi n g 
res ol ve d d uri n g a brief treat me nt i nterr u pti o n.  N o treat me nt -relate d or cli nicall y rele va nt tre n ds i n t he 
a nal ysis of safet y la b orat or y a n d 1 2 -lea d electr ocar di o gra m ( E C G) para meters were o bser ve d.  M ore 
s pecificall y, t here were n o a b n or malities i n L F Ts n or a n y tre n ds i n c ha n ges i n L F T para meters, n ote d i n 
eit her st u d y.  L F T a b n or malities, s pecificall y i ncreases i n li ver tra nsa mi nases, were see n i n 1 0 % t o 1 5 % 
of patie nts i n a pri or st u d y i n patie nts wit h R A at a d ose of 2 5 0  m g BI D f or 3 m o nt hs .  D ue t o t he use of 
differe nt f or m ulati o ns i n t he R A st u dies, t he plas ma dr u g c o nce ntrati o ns were 4 - t o 5-f ol d hi g her t ha n i n 
t he P hase 2a mil d A D st u dies. 
T h e 4 0  m g BI D  d ose  is c urre ntl y bei n g teste d i n a n o n g oi n g, bli n de d  P hase 2 b st u d y of 1 5 2  mil d A D 
patie nts.  O ne u nrelate d S A E ha s bee n re p orte d t o date a n d t he maj orit y of e ve nts ha ve bee n mil d t o 
m o derate  A Es  a n d u nrelate d t o st u d y dr u g .  O ne e ve nt of li ver tra nsa mi nase i ncrease t o > 3 ti mes t he 
u p per li mit of n or mal has bee n re p orte d.  T he patie nt  ha d n o ot her ill ness or s y m pt o ms , ha d a hist or y of 
m o derate alc o h ol i nta ke, a n d t he tra nsa mi nase le vels be ga n t o  res ol ve d uri n g c o nti n ue d st u d y dr u g 
a d mi nistrati o n.  St u d y dr u g is c urre ntl y i nterr u pte d , a n d t he s u bject’s treat me nt assi g n me nt has n ot bee n 
u n bli n de d .  
T he 4 0 m g BI D d ose le vel pr o vi des a 5 -f ol d mar gi n base d o n plas ma dr u g le vels t o n o a d verse effect 
le vel a n d 1 0-f ol d mar gi n t o mi ni mal a n d/ or e q ui v ocal fi n di n gs f or he mat ol o gical, he patic a n d 
ne ur o pat h ol o gical c ha n ges i n c hr o nic ( 9 - a n d 1 2-m o nt h) d o g t o xic ol o g y st u dies .  F urt her details are 
pr o vi de d i n t he i n vesti gat or br oc h ure.  


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S E L E C TI O N O F S T U D Y P O P U L A TI O N  
4. 1.  
I ncl usi o n Criteri a 
S u bjects meeti n g all of t he f oll o wi n g criteria are eli gi ble f or e nr oll me nt i n t his st u d y:  
1.  Me n a n d w o me n a ge 3 0 t o 7 0 years, i ncl usi ve.  
2.  Willi n g a n d a ble t o pr o vi de i nf or me d c o nse nt.  
3.  M ust ha ve ge neticall y c o nfir me d H D a n d i de ntifie d c o g niti ve deficits : 
a. Sta ge 1, as defi ne d b y U nifie d H u n ti n gt o n's Disease Rati n g Scale ( U H D R S) T otal F u ncti o nal 
Ca pacit y ( T F C) sc ore ≥9 , a n d 
b.  C A N T A B Paire d Ass ociate Lear ni n g T otal A dj uste d Err or Sc ore of > 1 6.  
4.  N or mal or c orrecte d e ye si g ht a n d a u dit or y a bilities, s ufficie nt t o perf or m all as pects of t he 
c o g niti ve a n d f u ncti o nal assess me nts.  
5.  N o hist or y of lear ni n g diffic ulties t hat ma y i nterfere wit h t he s u bject’s a bilit y t o c o m plete t he 
c o g niti ve tests.  
4. 2.  
E xcl usi o n Criteri a  
S u bjects meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or e nr oll me nt i n t his st u d y: 
1.  A  pr ofile of i m pair me nt t hat is n ot c o nsiste nt wit h H D.  
2.  Dia g n osis of a n y ot her o n g oi n g C N S  c o n diti o n ot her  t ha n H D , i ncl u di n g, b ut  n ot  li mite d t o, 
vasc ular  de me ntia,  de me ntia  wit h  Le w y  b o dies,  a n d Par ki ns o n’s  disease.  
3.  S uici dalit y,  defi ne d  as acti ve s uici dal t h o u g hts wit hi n  6  m o nt hs  bef ore  Scree ni n g  or  at 
Baseli ne,  defi ne d  as a ns weri n g yes  t o ite ms 4 or  5 o n  t he C ol u m bia -S uici de  Se verit y  Rati n g  
Scale  ( C-S S R S),  or  hist or y  of  s uici de atte m pt i n pre vi o us  2 years,  or,  i n t he I n vesti gat or’s 
o pi ni o n,  at seri o us ris k of  s uici de. 
4.  O n g oi n g  maj or  a n d acti ve ps yc hiatric  dis or der, m o derate  t o se vere de pressi ve  s y m pt o ms, a n d/ 
or  ot her  c o nc urre nt me dical  c o n diti o n t hat, i n t he o pi ni o n  of  t he I n vesti gat or, mi g ht  
c o m pr o mise safet y a n d/ or c o m plia nce wit h  st u d y re q uire me nts. 
5.  Dia g n osis  of  alc o h ol or  dr u g  a b use wit hi n  t he pre vi o us  2 years.  
6.  P o orl y  c o ntr olle d cli nicall y si g nifica nt me dical  ill ness, s uc h as h y perte nsi o n  ( bl o o d press ure  
> 1 8 0 m m H g  s yst olic or  1 0 0  m m H g  diast olic);  m y ocar dial  i nfarcti o n wit hi n  6 m o nt hs;  
u nc o m pe nsate d  c o n gesti ve heart  fail ure or  ot her  si g nifica nt car di o vasc ular, p ul m o nar y,  re nal, 
li ver, i nfecti o us disease,  i m m u ne dis or der,  or  meta b olic/e n d ocri ne  dis or ders  or  ot her  disease  
t hat w o ul d  precl u de  treat me nt wit h  a MA P  ki nase  i n hi bit or a n d/ or assess me nt of  dr u g  safet y 
a n d efficac y. 
7.  A ne mia wit h a he m o gl o bi n ≤1 0 g/ d L, cli nicall y si g nifica nt t h yr oi d f u ncti o n a b n or malit y, 
electr ol yte a b n or malities.  
8.  A S T  or  A L T > 1 . 5 × t he u p per  li mit of  n or mal  ( U L N), t otal bilir u bi n  > 1. 5  × U L N,  a n d/ or 
I nter nati o nal N or malize d  Rati o  (I N R) > 1. 5.  


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9.  K n o w n h u ma n  i m m u n o deficie nc y vir us ; or acti ve he patitis  B  or he patitis  C  vir us  i nfecti o n; 
e vi de nce acti ve or late nt t u berc ul osis. 
1 0.  S u bject  partici pate d  i n a st u d y of  a n i n vesti gati o nal dr u g  less t ha n 3 m o nt hs  or  5 half -li ves of  a n 
i n vesti gati o nal dr u g,  w hic he ver  is l o n ger, bef ore  e nr oll me nt i n t his st u d y. 
1 1.  Hist or y of pre vi o us ne ur os ur ger y t o t he brai n.  
1 2.  Fe male s u bjects w h o are  pre g na nt or  breast -fee di n g. 
1 3.  Male  s u bjects wit h  fe male part ners  of  c hil d-beari n g  p ote ntial  w h o  are u n willi n g  or  u na ble  t o 
a d here t o c o ntrace pti o n re q uire me nts s pecifie d i n t he pr ot oc ol  (see Secti o n 5. 8 ). 
1 4.  Fe male  s u bjects w h o  ha ve  n ot  reac he d me n o pa use  or  ha ve  n ot  ha d  a h ysterect o m y  or  
bilateral  o o p h orect o m y/sal pi n g o -o o p h orect o m y  a n d are n ot willi n g or u na ble t o a d here t o 
c o ntrace pti ve re q uire me nts s pecifie d i n t he pr ot oc ol (see Secti o n 5. 8 ). 
1 5.  Re q uires c o nc o mita nt use of c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4 i n hi bit ors or a nti-t u m or necr osis fact or-
al p ha t hera pies d uri n g st u d y partici pati o n (see Secti o n 5. 7 ). 
1 6.  K n o w n aller g y t o a n y i n gre die nt of t he trial me dicati o n or place b o.  
4. 3.  
Re m o v al of S u bjects fr o m Tre at me nt  
I n acc or da nce wit h t he c urre nt re visi o n of t he Declarati o n of Helsi n ki a n d ot her a p plica ble re g ulati o ns, a 
s u bject has t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me a n d f or a n y reas o n wit h o ut prej u dice t o his or 
her f ut ure me dical care b y t he p h ysicia n or at t he i nstit uti o n .  A s u bject’s partici pati o n ma y als o be 
disc o nti n ue d b y t he I n vesti gat or or S p o ns or  d ue t o c o m plia nce, safet y, or ot her a d mi nistrati ve reas o n  (see 
als o Secti o n  6. 2. 1 0 ). 
T he s u bject m ust  be disc o nti n ue d fr o m t he st u d y f or t he o cc urre nce of a n u nacce pta ble t o xicit y , i ncl u di n g 
a n y of t he f oll o wi n g:  
•  
A n y cli nicall y si g nific a nt i nfecti o n.  ( Cli nicall y si g nifica nt is defi ne d as a n y i nfecti o n re q uiri n g 
h os pitalizati o n a n d/ or i ntra ve n o us a nti bi otics a n d/ or c o nsi dere d t o be o p p ort u nistic.)  
•  
A L T or A S T > 8 × U L N ; A L T or A S T > 5 × U L N f or  > 2 wee ks ; or A L T or A S T > 3 × U L N a n d t otal 
bilir u bi n  > 2 × U L N or I N R > 1. 5 ; or A L T or A S T > 3 × U L N wit h t he a p peara nce of w orse ni n g of 
fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h, or e osi n o p hilia. 
Refer t o Secti o n  3. 1. 3  f or details re gar di n g f oll o w-u p after earl y disc o nti n uati o n .  A d diti o nal care a n d 
treat me nt will be pr o vi de d t o s u bjects o nce st u d y disc o nti n uati o n , i ncl u di n g a n y re q uire d f oll o w-u p visits 
f or res ol uti o n f or st u d y-relate d A E s, is c o m plete d.   
U p t o f o ur su bjects w h o wit h dra w fr o m t he st u d y treat me nt a n d / or st u d y pri or t o c o m pleti n g st u d y 
assess me nts at Wee k 4 of t he sec o n d treat me nt peri o d ma y  be re place d.   


EI P 1 9 -N F D -4 0 1, Versi o n 3. 0, 3 0  J uly, 2 0 1 9 
P a ge 2 4  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
5.  
T R E A T M E N T S  A D MI NI S T E R E D  
Nefla ma pi m o d 4 0  m g  ca ps ule(s) or matc hi n g place b o ca ps ules will be a d mi nistere d oral l y, BI D  wit h a 
meal or s nac k i n 2 treat me nt peri o ds of 1 0 wee ks  eac h.  D oses s h o ul d be ta ke n wit hi n 3 0 mi n utes  
f oll o wi n g a meal or s nac k  (i.e., brea kfast a n d di n ner) n o less t ha n 8 h o urs a part a n d at a p pr o xi matel y  t he 
sa me ti mes eac h da y t hr o u g h o ut t he st u d y. 
All s u bje cts will recei ve matc he d ( b y size a n d c ol or) ca ps ules t hat c o ntai n  4 0  m g nefla m api m o d or 
place b o , res pecti vel y. 
T he first d ose of st u d y dr u g i n eac h treat me nt peri o d will be a d mi nistere d at t he st u d y ce ntre.  
T he I n vesti gat or or ot her desi g nate d, q ualifie d site pers o n nel s h o ul d re vie w d osi n g i nstr ucti o ns wit h t he 
s u bject.  S u bjects will be i nstr ucte d t o ret ur n all st u d y c o ntai ners, re gar dless of w het her e m pt y o r 
c o ntai ni n g u n use d st u d y dr u g.  
5. 1.  
P ac k a gi n g a n d L a beli n g  
EI P P har ma w ill s u p pl y place b o or nefla m api m o d  ca ps ules o n a n i n di vi d ual s u bject basis .   
B ot h nefla m api m o d a n d place b o ca ps ules  are o pa q ue i n c ol or .  La bel details will be i n acc or da nce wit h 
l ocal a n d nati o nal re q uire me nts.  
5. 2.  
St u d y Dr u g S u p pl y, St or a ge , a n d H a n dli n g  
S t u d y dr u g will be s u p plie d t o t he site o n a n i n di vi d ual  s u bject basis.  
Nefla ma pi m o d ca ps ules s h o ul d be st ore d at r o o m te m perat ure.  
W hile at t he cli nical site, st u d y dr u g access s h o ul d be li mite d t o t he I n vesti gat or a n d ot her q ualifie d site 
pers o n nel . 
5. 3.  
Dr u g Acc o u nt a bilit y, Dis p os al, Ret ur n, or Rete nti o n of U n use d 
St u d y Dr u g  
T he site desi g nate d p har macist or ot her q ualifie d pers o n nel wil l d oc u me nt recei pt fr o m S p o ns or , 
dis pe nsi n g t o s u bjects, a n d ret ur n t o site fr o m s u bject  o n t he dr u g acc o u nta bilit y l o g(s) .   
S u bjects will be i nstr ucte d t o ret ur n all blister pac ks , re gar dless of w het her e m pt y or c o ntai ni n g u n use d 
st u d y dr u g.  EI P P har ma or desi g nee will re vie w acc o u nta bilit y rec or ds t hr o u g h o ut t he c o n d uct of t he 
st u d y.  
T he site s h o ul d mai ntai n all st u d y dr u g c o ntai ners ( use d a n d u n use d) u ntil fi nal re vie w of acc o u nta bilit y is 
c o n d ucte d b y t he EI P P har ma or desi g nee , a n d i nstr ucti o ns re gar di n g ret ur n or dis p osal, as a p plica ble, are 
pr o vi de d.   
5. 4.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nt Gr o u p  
After s u bjects ha ve c o m plete d S cree ni n g V isit a n d are dee me d eli gi ble , t he y will be ra n d o mize d i n a 
bli n de d ma n ner t o  recei ve eit her a) nefla ma pi m o d f or 1 0 wee ks f oll o we d b y place b o f or 1 0 wee ks or 
b)  place b o f or 1 0 wee ks f oll o we d b y nefla ma pi m o d f or 1 0 wee ks utilizi n g a ma n uall y ge nerate d ra n d o m 
c o de.   


EI P 1 9 -N F D -4 0 1, Versi o n 3. 0, 3 0  J uly, 2 0 1 9 
P a ge 2 5  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
5. 5.  
St u d y Bli n di n g  a n d Bre a ki n g t he Bli n d  
S u bjects a n d site pers o n nel as s ociate d wit h st u d y c o n d uct will be bli n de d t o treat me nt assi g n me nt.  
Treat me nt c o des will be pr o vi de d i n seale d e n vel o pes t o t he site a n d will be st ore d b y t he p har macist or 
desi g nee.  
D uri n g t he c o n d uct of t he st u d y, t he bli n d s h o ul d be br o ke n o n a n i n di vi d ual s u bject basis i n t he e ve nt of 
a n e mer ge nc y w here it is necessar y f or t he I n vesti gat or t o k n o w w hic h treat me nt t he s u bject is recei vi n g 
bef ore t he s u bject ca n be treate d.  T he c o de  ma y als o be br o ke n if s o me o ne n ot i n t he st u d y uses st u d y 
dr u g (e. g ., if a c hil d i n t he partici pa nt’s h o use h ol d ta kes st u d y dr u g, t he bli n d ma y be br o ke n t o deter mi ne 
treat me nt f or t he c hil d.)  
W he n it is necessar y t o brea k t he bli n d, t he researc her ma y u n bli n d t he treat me nt i m me diatel y 
(i.e., wit h o ut pri or n otice t o t he M e dical M o nit or, S p o ns or, or ot her) b ut m ust n otif y t he I n de pe n de nt 
Et hics C o m mittee (I E C) , as per l ocal re g ulati o ns, a n d S p o ns or as s o o n as p ossi ble, prefera bl y b y 
tele p h o ne a n d t he n i n writi n g, re gar di n g t he necessit y of c o de brea ki n g.  
If t he c o de is br o ke n f or a s u bject, t his m ust be d oc u me nte d i n t he electr o nic case re p ort f or m ( eC R F) a n d 
s o urce d oc u me nts, t o get her wit h t he reas o ns f or brea ki n g t he c o de. 
5. 6.  
D ose M o dific ati o n f or T o xicit y  
N o d ose m o dificati o ns a re per mitte d d uri n g t he st u d y.  If a s u bject is u na ble t o t olerate t he assi g ne d st u d y 
dr u g d ose t he n t he s u bject s h o ul d be disc o nti n ue d fr o m st u d y dr u g treat me nt (Secti o n  4. 3 ). 
5. 7.  
P ri or a n d C o nc o mit a nt T her a p y  
A n y me dicati o ns ta ke n fr o m Scree ni n g t hr o u g h t he Fi nal St u d y Visit , i ncl u di n g all prescri pti o n a n d o ver-
t he-c o unter me dicati o ns as well as s u p ple me nts,  will be d oc u me nte d i n t he s u bject’s s o urce d oc u me nt a n d 
in t he eC R F.  
W hile dr u g -dr u g i nteracti o n st u dies ha ve n ot bee n c o n d ucte d, i n vitr o testi n g i n dicates t hat nefla ma pi m o d 
is meta b olize d b y o xi dati o n i n t he li ver b y t he C Y P s yste m (c o m bi nati o n of C Y P 3 A 4 a n d C Y P 2 C 1 9 
is oz y mes).  U ntil t he meta b olis m is better c haracterize d, c o nc o mit a nt str o n g i n hi bit ors of C Y P 3 A 4 are 
pr o hi bite d a n d str o n g i n d ucers of C Y P 3 A 4 s h o ul d be use d wit h c a uti o n i n s u bjects recei vi n g 
nefla ma p i m o d, as t he use of s uc h dr u gs c o ul d i m pact nefla ma pi m o d meta b olis m i n s u bjects w h o ha ve a n 
u n derl yi n g C Y P 2 C 1 9 ge n ot y pic varia nt t hat i m p acts acti vit y of t hat C Y P 2 C 1 9.   
T he f oll o wi n g me dic ati o ns are pr o hi bite d d uri n g st u d y p artici p ati o n:  
•  
Str o n g C Y P 3 A 4 i n hi bit ors (see  Ta ble 5 -1 ). 
•  
A n y o t her i n vesti gati o nal dr u g.  If a s u bject has pre vi o usl y partici pate d i n a st u d y of a n 
i n vesti gati o nal dr u g, last d osi n g m ust ha ve occ urre d 3 m o nt hs or 5 half -li ves of t he i n vesti gati o n 
dr u g, w hic he ver is l o n ger, bef ore e nr oll me nt i n t his st u d y.  
•  
Li ve vacci nes, wit h t he e xce pti o n of i nfl ue nza d uri n g st u d y partici pati o n a n d t hr o u g h 3 m o nt hs 
after t he last st u d y dr u g  d ose.  
•  
A n y a nti -t u m or necr osis fact or-al p ha t hera p y.  


EI P 1 9 -N F D -4 0 1, Versi o n 3. 0, 3 0  J uly, 2 0 1 9 
P a ge 2 6  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
T he Me dical M o nit or s h o ul d be c o ntacte d wit h a n y q uesti o ns re gar di n g c o nc o mita nt use of me dicati o ns 
t hat are t h o u g ht t o m o d ulate C Y P 3 A 4 acti vit y. 
T a ble 5 -1 : 
C Y P 3 A 4 I n hi bit ors  (Str o n g  are Pr o hi bite d)  
Str o n g I n hi bit ors  
≥5 -f ol d i ncre ase i n A U C  
or  > 8 0 % decre ase i n C L  
M o der ate i n hi bit ors  
≥2 b ut < 5 -f ol d i ncre ase i n A U C 
or  5 0 -8 0 % decre ase i n C L  
We a k i n hi bit ors  
≥1. 2 5 b ut < 2 -f ol d i ncre ase i n A U C 
or  2 0 -5 0 % decre ase i n C L  
b oce pre vir  
c o bicistat 
clarit hr o m yci n  
c o ni va pta n 
da n o pre vir/rit o na vir  
diltiaze m  
el vite gra vir/rit o na vir  
gra pefr uit j uice  
i delalisi b 
i n di na vir/rit o na vir  
itrac o naz ole 
ket oc o naz ole  
l o pi na vir/rit o na vir 
nefaz o d o ne  
nelfi na vir  
parita pre vir/rit o na vir/ o m bitas vir  
p osac o naz ole  
rit o na vir  
sa q ui na vir/rit o na vir  
tela pre vir 
ti pra na vir/rit o na vir 
tr olea n d o m yci n 
v oric o naz ole  
A pre pita nt  
ci meti di ne 
ci pr ofl o xaci n  
cl otri maz ole  
criz oti ni b 
c ycl os p ori ne  
dr o ne dar o ne  
er yt hr o m yci n  
fl uc o naz ole 
fl u v o xa mi ne 
i mati ni b 
t ofis o pa m 
vera pa mil  
c hl orz o xaz o ne  
cil ostaz ol 
f osa pre pita nt 
istra def ylli ne 
i vacaft or 
l o mita pi de 
ra niti di ne 
ra n olazi ne 
tacr oli m us 
tica grel or 
 
 


EI P 1 9 -N F D -4 0 1, Versi o n 3. 0, 3 0  J uly, 2 0 1 9 
P a ge 2 7  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
T a ble 5 -2 : 
C Y P 3 A 4 I n d ucers  (t o be Use d wit h C a uti o n) 
Str o n g I n d ucers  
≥8 0 % decre ase i n A U C  
M o der ate I n d ucers  
5 0 -8 0 % decre ase i n A U C  
We a k I n d ucers  
2 0 -5 0 % decre ase i n A U C  
car ba maze pi ne e nzal uta mi de  
mit ota ne  
p he n yt oi n  
rifa m pi n 
St. J o h n’s w ort  
b ose nta n  
efa vire nz 
etra viri ne 
m o dafi nil  
 
ar m o dafi nil  
r ufi na mi de 
A b bre vi ati o ns:  A U C, area u n der t he c o nce ntrati o n -ti me c ur ve 
5. 8.  
C o ntr ace pti o n a n d Pre g n a nc y  
T his secti o n s h o ul d be rea d i n c o nj u ncti o n wit h t he selecti o n criteri a t hat relate t o a ge a n d c o ntrace pti o n: 
•  
I ncl usi on criteri o n # 1 ( Secti o n  4. 1 ) a n d E xcl usi o n criteria  # 1 3  a n d #1 4  (Secti o n  4. 2 ) 
N o si g ns of e m br y o -fetal t o xicit y or terat o ge nic effects of nefla ma pi m o d were o bser ve d i n rats.  Testi n g 
i n ra b bits was n ot perf or me d d ue t o lac k of e x p os ure f oll o wi n g a d mi nistrati o n of t he nefla ma pi m o d  
f or m ulati o n.  N o h u ma n st u dies of effects of nefla ma pi m o d  o n c o nce pti o n, pre g na nc y, or lactati o n ha ve 
bee n perf or me d.  Fe males s h o ul d n ot be e x p ose d t o nefla ma pi m o d  if pre g na nt, breastfee di n g, or 
atte m pti n g t o c o ncei ve.  T he f oll o wi n g g ui deli nes f or c o ntr ace pti o n s h o ul d be f oll o we d fr o m bef o re first 
d ose o n Da y  1 t hr o u g h 9 1 da ys f oll o wi n g t he last d ose of st u d y dr u g:  
Fe male s u bjects of c hil d -beari n g p ote ntial ( ha ve n ot e x perie nce d me n o pa use a n d ha ve n ot ha d a 
h ysterect o m y or bilateral o o p h orect o m y/sal pi n g o -o o p h orect o m y)  or f e male s u bjects w h o ha ve 
e x perie nce d me n o pa use wit hi n t he pre vi o us year m ust ha ve a ne gati ve pre g na nc y test d uri n g Scree ni n g 
a n d e ver y f o ur wee ks d uri n g t he 1st a n d 2 n d treat me nt peri o ds a n d m ust use  a barrier met h o d of 
c o ntrace pti o n i n a d diti o n t o  at least 1 of t he f oll o wi n g c o ntrace pti ve met h o ds: c o m plete a bsti ne nce 
re gar dless of me nstr ual c ycle ti mi n g, c o ntrace pti ve ( oral, tra ns der mal, i njecta ble, or i m pla nta ble), or 
i ntra uteri ne de vice. 
Male s u bje cts wit h fe male part ners of c hil d -beari n g p ote ntial m ust use  a barrier met h o d of c o ntrace pti o n 
i n a d diti o n t o at least 1 of t he f oll o wi n g c o ntrace pti ve met h o ds:  h or m o nal c o ntrace pti ves ( oral, i njecta ble, 
patc h, i ntra uteri ne de vices), male sterilizati o n, or  t otal a bsti ne nce fr o m heter ose x ual i nterc o urse, w he n 
t his is t he preferre d a n d us ual lifest yle of t he s u bject. 
•  
A bsti ne nce is defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k 
ass ociate d wit h t he st u d y treat me nts w he n t hi s is t he preferre d a n d us ual lifest yle of t he s u bject.  
N ote t hat peri o dic a bsti ne nce (cale n dar, s y m pt ot her mal, p ost -o v ulati o n met h o ds), wit h dra wal 
(c oit us i nterr u pt us), s per mici des o nl y, a n d lactati o nal a me n orr h oea met h o d are n ot acce pta ble 
met h o ds of c o n trace pti o n. 
A n y p re g na nc y s h o ul d be re p orte d t o t he I n vesti gat or, a n d, i n t ur n, t he pre gna nc y s h o ul d be re p orte d t o 
V oisi n C o ns ulti n g  Life Scie nces wi t hi n 2 4 h o urs of t he I n vesti gat or’s a ware ness of t he pre g na nc y.  If a 


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P a ge 2 8  of 5 0  
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C o nfi de nti al  
fe male s u bject bec o mes pre g na nt, st ud y dr u g will be per ma ne ntl y disc o nti n ue d a n d t he s u bject will be 
disc o nti n ue d fr o m t he st u d y.  
Wit h pr o per i nf or me d c o nse nt (se parate pre g na nc y i nf or me d c o nse nt f or m), t he s u bject or part ner will be 
f oll o we d t hr o u g h t he c o m pleti o n of t he pre g na nc y a n d o utc ome of t he pre g na nc y re p orte d, a n d t he i nfa nt 
will be f oll o we d f or 1 2  m o nt hs after birt h.  
5. 9.  
Acti vit y Restricti o ns  
T he I n vesti gat or is t o a d vise s u bjects t o ta ke meas ures t o mi ni mize e x p os ure t o ultra vi olet li g ht d uri n g  
st u d y partici pati o n t hr o u g h 2 wee ks after t he last st u d y dr u g d ose.  
5. 1 0.  
Tre at me nt C o m pli a nce  
Treat me nt c o m plia nce will be assesse d b y re vie wi n g t he c o u nt of ret ur ne d ca ps ules  at eac h visit.  A n y 
a p pare nt discre pa ncies bet wee n q ua ntit y of ca ps ules ret ur ne d a n d t he n u m ber e x pecte d base d o n d osi n g 
sc he d ule will be disc usse d wit h t he s u bject t o e ns ure a n u n dersta n di n g of d osi n g i nstr ucti o ns.  
Re peate d n o n -c o m plia nce wit h d osi n g i nstr ucti o ns ma y ne cessitate disc o nti n uati o n fr o m t he st u d y, base d 
o n t he I n vesti gat or’s j u d g me nt (Secti o n  4. 3 ). 


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P a ge 2 9  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
6.  
S T U D Y  A S S E S S M E N T S A N D P R O C E D U R E S  
6. 1.  
Sc he d ule of Assess me nts  
T he sc he d ule of assess me nts is prese nte d i n  Ta ble  6 -1 . 


 EI P 1 9 -N F D -4 0 1, Versi o n 3. 0, 3 0 J uly, 2 0 1 9 
P a ge 3 0  of 5 0  
 
EI P P h ar m a, I nc  
C o nfi de nti al  
T a ble  6 -1  
Sc he d ule of Assess me nts  
E v al u ati o n  
Scree ni n g a 
Tre at me nt Peri o d 1  
W as h o ut  
( 8 t o 1 2 
wee ks)  
Tre at me nt Peri o d 2  
E T 
Visit c 
Fi n al St u d y 
Visit d  
Wit hi n 
2 1  d a ys of 
D 1  
W 0
b  
W 4  
( ±4 d ) 
W 8  
( ±4 d ) 
W 1 0  
( ±2 d ) 
2 w ks ( ± 3 d) of 
l ast d ose i n  
Peri o d 1  
W 0
b  
W 4  
( ±4 d ) 
W 8  
( ±4 d ) 
W 1 0  
( ±2 d ) 
Wit hi n 
3  d after 
l ast d ose 
2 w ks ( ± 3  d) 
of l ast d ose  
I nf or me d C o nse nt 
X
Pe 
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y 
re vie w 
X  
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y testi n g  
X
Pf 
X  
X  
X  
 
 
X  
X  
X  
 
 
X  
P h ysical 
e xa mi nati o n
Pg 
X  
 
 
 
X  
 
X  
 
 
X  
X  
X  
C -S S R S  
X  
 
 
 
X  
 
X  
 
 
X  
 
 
H os pital A n xiet y 
a n d De pressi o n 
Scale  
X  
 
X  
 
X  
 
X  
X  
 
X  
 
 
U H D R S  
X  
 
 
 
X  
 
X  
 
 
X  
 
 
C A N T A B  
X  
X  
X  
 
X  
 
X  
X  
 
X  
X  
 
M W M  
X  
X  
X  
 
X  
 
X  
X  
 
X  
X  
 
Vital si g ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Pri or/c o nc o mita nt 
me dicati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse e ve nts 
rec or di n g Ph 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
He mat ol o g y a n d 
c he mistr y i 
X  
X  
X  
X  
 
X  
X  
X  
X  
 
 
X  
1 2 -lea d 
electr ocar di o gra m j 
X  
 
 
 
 
 
 
 
 
 
 
 


EI P 1 9 -N F D -4 0 1, Versi o n 3. 0, 3 0  J uly, 2 0 1 9 
P a ge 3 1  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
E v al u ati o n  
Scree ni n g a 
Tre at me nt Peri o d 1  
W as h o ut  
( 8 t o 1 2 
wee ks)  
Tre at me nt Peri o d 2  
E T 
Visit c 
Fi n al St u d y 
Visit d  
Wit hi n 
2 1  d a ys of 
D 1  
W 0
b  
W 4  
( ±4 d ) 
W 8  
( ±4 d ) 
W 1 0  
( ±2 d ) 
2 w ks ( ± 3 d) of 
l ast d ose i n  
Peri o d 1  
W 0
b  
W 4  
( ±4 d ) 
W 8  
( ±4 d ) 
W 1 0  
( ±2 d ) 
Wit hi n 
3  d after 
l ast d ose 
2 w ks ( ± 3  d) 
of l ast d ose  
Dis pe nse st u d y 
dr u g k 
 
X  
X  
X  
 
 
X  
X  
X  
 
 
 
Fi nal st u d y dr u g 
rec o nciliati o n 
 
 
 
 
X  
 
 
 
 
X  
X  
 
C A N T A B = Ca m bri d ge Ne ur o ps yc h ol o gical Test A ut o mate d Batter y; C -S S R S:  C ol u m bia -S uici de Rati n g Scale; D = D a y; E T = E n d -of -Treat me nt; M W M = M orris Water Maze ; 
U H D R S = U nifie d H u nti n gt o n's Disease Rati n g Scale ; W = Wee k. 
N ote: Tele p h o ne c o ntacts will be c o n d ucte d t o deter mi ne s u bject stat us a n d assess c o m plia nce bet wee n W 0 a n d W 4 a n d  bet wee n W 4 a n d W 8 of eac h Treat me nt Peri o d.  
a. 
All scree ni n g assess me n ts s h o ul d be c o n d ucte d wit hi n 2 1  da ys  of Da y  1.  
b.  
At Wee k 0 of eac h treat me nt peri o d , all pr oce d ures s h o ul d be c o n d ucted pri or t o first d ose of st u d y dr u g. 
c. 
S u bjects w h o pre mat urel y disc o nti n ue st u d y dr u g f or a n y reas o n will be as ke d t o ret ur n t o t he cli nical site f or a n Earl y Ter m i nati o n visit wit hi n 3 da ys f oll o wi n g t he last st u d y 
dr u g d ose; if it is deter mi ne d t hat t he  s u bject will disc o nti n ue st u d y dr u g w hile at t he st u d y ce nter f or a sc he d ule d visit, t he n t he Earl y Ter mi nati o n visit s h o ul d be c o n d ucte d 
at t hat ti me.   
d.  
T he F oll o w -u p Visit s h o ul d be c o n d ucte d wit hi n 2 wee ks  ( ± 3 da ys ) of t he last d ose of st u d y dr u g f or s u bjects w h o c o m plete t he st u d y or disc o nti n ue earl y. 
e. 
I nf or me d c o nse nt pr oce d ures, i ncl u di n g si g ni n g of i nf or me d c o nse nt, m ust be c o m plete d bef ore a n y st u d y-s pecific pr oce d ures are perf or me d. 
f. 
Fe male s u bjects  of c hil d -be ari n g p ote ntial or  w h o ha ve reac he d me n o pa use i n t he pre vi o us year m ust ha ve a ser u m or uri ne pre g na nc y test perf or me d  d uri n g Scree ni n g , W 0 ,  
e ver y 4 wee ks d uri n g  t he 1st a n d 2 n d  treat me nt peri o ds , a n d at t he F oll o w-u p Visit ; s u bjects wit h p ositi ve res ults are n ot eli gi ble f or st u d y partici pati o n.  
g.  
Refer t o Secti o n  6. 2. 7  f or details re gar di n g p h ysical e xa mi nati o n.  
h.  
Defi niti o ns a n d pr oc e d ures f or d oc u me nti n g a n d re p orti n g A Es seri o us a d verse e ve nts ( S A Es) are pr o vi de d i n Secti o n  7 . 
i. 
Details of cli nical la b orat or y sa m pli n g f or c he mistr y a n d he mat ol o g y , are disc usse d i n Secti o n  6. 2. 9 .  
j. 
Details of 1 2 -lea d E C G assess me nt are disc usse d i n Secti o n  6. 2. 8 . 
k.   
St u d y dr u g details i ncl u di n g pac ka gi n g, st ora ge, acc o u nta bilit y, a n d d osi n g are prese nte d i n Secti o n  5 . 


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EI P P h ar m a, I nc  
C o nfi de nti al  
6. 2.  
St u d y Assess me nts  
6. 2. 1.  
Baseli ne a n d Disease C haracteristics   
Details re gar di n g H D hist or y will be c ollecte d d uri n g Scree ni n g, as s pecifie d in t he eC R F.  
6. 2. 2.  
C ol u m bia -S uici de Se verit y Rati n g Scale  
T he C -S S R S is a cli nicia n -a d mi nistere d i nstr u me nt t hat assesses s uici dal i deati o n a n d be ha vi or ( 3 8 TP os ner  et 
al, 2 0 1 13 8 T).  T he “ Baseli ne” versi o n of t he i nstr u me nt will be a d mi nistere d t o s u bjects  d uri n g Scree ni n g  
a n d bef ore  be gi n ni n g t he sec o n d treat me nt peri o d , a n d t he “ Si nce Last Visit” versi o n will be use d at all 
ot her ti me p oi nts s pecifie d i n Ta ble  6 -1 . 
6. 2. 3.  
H os pital A n xiet y a n d De pressi o n Scale  
T he H os pital A n xiet y a n d De pressi o n Scale is a 1 4 -ite m self-assess me nt scale desi g ne d t o deter mi ne t he 
de gree of a n xiet y a n d de pressi o n a patie nt is e x perie nci n g ( Zi g m o n d, S nait h, 1 9 8 3 ).  Eac h ite m o n t he 
q uesti o n naire is sc ore d fr o m 0 -3 ; t h us t otal sc ores ra n ge fr o m 0 a n d 2 1 f or eit her a n xiet y or de pressi o n .  
T h e H os pital A n xiet y a n d De pressi o n Scale is t o be c o m plete d at t he ti me p oi nts s pecifie d i n  Ta ble  6 -1 .  
6. 2. 4.  
U nifie d H u nti n gt o n's Disease Rati n g Scale   
T he U H D R S was de vel o pe d as a cli nical rati n g scale t o assess 4  d o mai ns of cli nical perf or ma nce a n d 
ca pacit y i n H D: m ot or f u ncti o n, c o g niti ve f u ncti o n, be ha vi oral a b n or malities, a n d f u ncti o nal ca pacit y 
(H u nti n gt o n St u d y Gr o u p, 1 9 9 6 ).  
•  
T he  m ot or secti o n  of t he U H D R S assesses m ot or feat ures of H D wit h sta n dar dize d rati n gs of 
oc ul o m ot or f u ncti o n, d ysart hria, c h orea, d yst o nia, gait, a n d p ost ural sta bilit y .  A de m o nstrati o n of 
t he tec h ni q ues of t he m ot or e xa m a n d e xa m ples of eac h gra de of ab n or malit y are pr o vi de d o n t he 
acc o m pa n yi n g vi de ota pe .  T he t otal m ot or i m pair me nt sc ores is t he s u m of all t he i n di vi d ual 
m ot or rati n gs, wit h hi g her sc ores i n dicati n g m ore se vere m ot or i m pair me nt t ha n l o wer sc ores.  
•  
C o g niti ve o per ati o ns  are assesse d b y a p h o netic ver bal fl ue nc y test, S y m b ol Di git M o dalities 
Test, a n d t he Str o o p I nterfere nce Test .  T he Str o o p Test res ults are re p orte d as t he ra w n u m ber of  
c orrect a ns wers gi ve n i n a 4 5 -sec o n d peri o d .  Res ults  f or t he ot her tests are re p orte d as t he ra w 
n u m ber  of  c orrect res p o nses .  Hi g her sc ores i n dicate better  c o g niti ve perf or ma nce.  
•  
T he be h a vi or al assess me nt  meas ures t he fre q ue nc y a n d se verit y of s y m pt o ms relate d t o affect, 
t h o u g ht c o nte nt a n d c o pi n g st yles.  T he t otal be ha vi or sc ore is t he s u m of all res p o nses; h o we ver, 
t his sc ore ma y ha ve less usef ul ness t ha n t he i n di vi d ual s u bscale sc ores f or m o o d, be ha vi or, 
ps yc h osis,  a n d o bsessi ve ness w hic h are create d b y s u m mi n g t he res p o nses t o t he c orres p o n di n g 
q uesti o ns .  T he e val uat or is als o re q ueste d t o pr o vi de a cli nical i m pressi o n as t o w het her t he 
patie nt, at t he ti me of t he e val uati o n, has cli nical e vi de nce of c o nf usi o n, de me ntia, or de pressi o n 
a n d w het her t he patie nt re q uires a nti de pressa nt t hera p y, acc or di n g t o preset defi niti o ns i n t he 
e xa mi nati o n g ui deli nes .  Hi g her sc ores o n t he be ha vi or assess me nts i n dicate m ore se vere 
dist ur ba nce t ha n l o wer sc ores.  
•  
T he f uncti o n al assess me nts i ncl u de t he H D F C S, t he I n de pe n de nce scale, a n d a c hec klist of 
c o m m o n dail y tas ks .  F or t he latter ite ms, t he i n vesti gat or i n dicates if t he patie nt c o ul d perf or m 
t he tas k.  T he c hec klist is s u m me d b y gi vi n g a sc ore of 1 t o all “ yes” re p lies.  T he H D F C S is 


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re p orte d as t he t otal f u ncti o nal ca pacit y ( T F C) sc ore.  T he i n de pe n de nce scale is rate d fr o m 0 t o 
1 0 0, wit h hi g her sc ores o n t he f u ncti o n scales i n dicati n g better f u ncti o ni n g t ha n l o wer sc ores.  
T he U H D R S is t o be a d mi nistere d at t he ti me p oi nts s pecifie d i n Ta ble  6 -1 .   
6. 2. 5.  
C A N T A B  
T he C A N T A B batter y was de vel o pe d f or t he assess me nt of c o g niti ve deficits i n h u ma ns wit h 
ne ur o de ge nerati ve diseases or brai n da ma ge .  It c o nsists of a series of i nterrelate d c o m p uterize d tests of 
me m or y, atte nti o n, a n d e xec uti ve f u ncti o n, a d mi nistere d via a t o uc h -se nsiti ve scree n (Fra y a n d R o b bi ns, 
1 9 9 6 ).  S pecificall y, C A N T A B tests i ncl u de:   
•  
M ot or Scree ni n g Tas k: 2 mi n utes  
•  
Reacti o n Ti me  : 3 mi n utes 
•  
Paire d Ass ociates Lear ni n g: 8 mi n utes  
•  
O ne T o uc h St oc ki n gs of Ca m bri d ge: 1 0 mi n utes  
•  
S patial S pa n: 5 mi n utes  
•  
Patter n Rec o g niti o n Me m or y : 4  mi n utes  
T he C A N T A B is t o be a d mi niste re d at t he ti me p oi nts s pecifie d i n Ta ble  6 -1 .   
C A N T A B M ot or Scree ni n g T as k  ( M O T): 
T he M O T ser ves as a ge neral i ntr o d ucti o n t o t he C A N T A B batter y a n d p r o vi des a ge neral assess me nt of 
w het her se ns ori m ot or deficits or lac k of c o m pre he nsi o n, will li mit t he c ollecti o n of vali d data fr o m t he 
partici pa nt.  C ol o ure d cr osses are prese nte d i n differe nt l ocati o ns o n t he scree n, o ne at a ti me.  T he 
par tici pa nt m ust select t he cr oss o n t he scree n as q uic kl y a n d acc uratel y as p ossi ble. 
C A N T A B Re acti o n Ti me ( R TI):  
R TI pr o vi des a n assess me nt of m ot or a n d me ntal res p o nse s pee ds, as well as meas ures of m o ve me nt ti me, 
reacti o n ti me, res p o nse acc urac y a n d i m p ulsi vit y.  T he partici pa nt m ust select a n d h ol d a b utt o n at t he 
b ott o m of t he scree n .  Circles are prese nte d a b o ve ( o ne f or t he si m ple m o de, a n d fi ve f or t he fi ve -c h oice 
m o de. )  I n eac h case, a yell o w d ot will a p pear i n o ne of t he circles, a n d t he partici pant m ust react as s o o n 
as p ossi ble, releasi n g t he b utt o n at t he b ott o m of t he scree n, a n d selecti n g t he circle i n w hic h t he d ot 
a p peare d.  
C A N T A B P aire d Ass oci ate Le ar ni n g ( P A L):  
D uri n g t he P A L, partici pa nts are re q uire d t o re me m ber t he l ocati o ns of a n u m ber  of differe nt o bjects 
w hic h are hi d de n i nsi de b o xes o n t he c o m p uter scree n .  T his tas k re q uires t he partici pa nt t o lear n t o pair 
t w o ite ms i n me m or y - i n t his case t he t y pe of o bject a n d t he l ocati o n of t he o bject.  W he n o ne of t he 
paire d feat ures is re vea le d (i n t his case t he o bject), t he partici pa nt is as ke d t o re me m ber its ass ociate (t he 
l ocati o n it is hi d de n i n).  T his t y pe of lear ni n g is esse ntial i n e ver y da y life, f or e xa m ple w he n lear ni n g 
ne w w or ds .  W he n y o u lear n a ne w w or d, n ot o nl y d o y o u lear n t he w or d itself, b ut y o u ha ve t o pair t his 
wit h t he mea ni n g it re prese nts . 


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C o nfi de nti al  
C A N T A B S p ati al S p a n  ( S S): 
S S tests s patial me m or y s pa n b y meas uri n g a bilit y t o me m orise t he or der i n w hic h a n i ncreasi n g n u m ber 
of w hite b o xes c ha n ge c ol o ur.  T he s patial s pa n tas k r elies o n vis u os patial w or ki n g me m or y; t he 
c o m p o ne nt of w or ki n g me m or y t hat all o ws y o u t o te m p oraril y h ol d a n d ma ni p ulate i nf or mati o n a b o ut 
places.   Ma n y e ver y da y acti vities i n v ol ve vis u os patial w or ki n g me m or y, i ncl u di n g fi n di n g y o ur wa y 
ar o u n d y o ur e n vir o n me nt, j u d gi n g t he p ositi o n of ot her m ot orists w hile y o u are dri vi n g a n d searc hi n g f or 
y o ur ke ys.  Acc or di n g t o o ne ver y i nfl ue ntial c o g niti ve m o del  of w or ki n g me m or y ( Ba d derl y & Hitc h, 
1 9 7 4 ) vis u os patial w or ki n g me m or y de pe n ds o n a s pecialise d s u b-c o m p o ne nt of t he w or ki n g me m or y 
s yste m.  T his is referre d t o as t he “ vis u os patial s ketc h pa d” a n d is t h o u g ht t o ha ve a vis ual “cac he” , 
res p o nsi ble f or st ori n g vis ual f or m a n d c ol o ur i nf or mati o n, a n d a n “i n ner scri be” w hic h deals wit h s patial 
a n d m o ve me nt i nf or mati o n .  T his tas k places si g nifica nt de ma n ds o n t he i n ner scri be.   
C A N T A B O ne T o uc h St oc ki n gs of C a m bri d ge  ( O T S): 
E xec uti ve f u nc ti o ns are a set of c o g niti ve s kills t hat hel p us t o re g ulate t he ot her me ntal pr ocesses t hat are 
necessar y t o c o m plete e ver y da y acti vities .  T he y all o w us t o pr o d uce c o m ple x g oal directe d t h o u g hts a n d 
be ha vi o urs s uc h as pla n ni n g f ut ure e ve nts, carr yi n g o ut  tas ks wit h m ulti ple sta ges a n d o verc o mi n g 
ha bit ual res p o nses .  E xec uti ve f u ncti o ns pr o vi de us wit h t he a bilit y t o d y na micall y a dj ust a n d re g ulate 
be ha vi o ur o n t he basis of i nter nal re prese ntati o ns a n d e xter nal fee d bac k .  T he O T S meas ures t he 
e xec uti ve f u n cti o ns of s patial pla n ni n g a n d w or ki n g me m or y a bilit y .  T he patie nt is s h o w n t w o dis pla ys 
c o ntai ni n g t hree c ol o ure d balls, prese nte d s o t he y ca n be percei ve d as stac ks of c ol o ure d balls i n 
st oc ki n gs.  I n eac h trial, t he patie nt m ust i ma gi ne m o vi n g t he balls i n t he l o wer dis pla y t o c o p y t he patter n 
s h o w n i n t he u p per, a n d calc ulate h o w ma n y ‘ m o ves’ t his w o ul d ta ke.  Pla n ni n g a bilit y is i n de xe d b y t he 
n u m ber of pr o ble ms s ol ve d at t he first atte m pt at eac h le vel of diffic ult y .  T he O T S will be use d i n t his 
st ud y t o deter mi ne w het her perf or ma nce o n t he s ocialit y e x peri me nts has a n y relati o ns hi p t o deficits i n 
e xec uti ve f u ncti o n i n H D.   
C A N T A B P atter n Rec o g niti o n Me m or y  ( P R M) 
T he P R M is a test of vis ual rec o g niti o n me m or y  a n d is li n ke d t o hi p p oca m pal f u ncti o n ( O we n et al, 
1 9 9 5 ).  I n t he e nc o di n g p hase, partici pa nts are s h o w n a series of abstract li ne dra wi n gs prese nte d o ne at a 
ti me i n t he ce ntre of a bla n k scree n.  T he y are i nstr ucte d t o re me m ber t he patter ns.  D uri n g t he 
rec o g niti o n p hase, t w o a bstract li ne dra wi n gs are prese nte d o n t he scree n, si de b y si de a n d participa nts are 
as ke d t o i de ntif y t he o ne t he y ha ve pre vi o usl y bee n s h o w n .  Vis ual rec o g niti o n me m or y is i n de xe d b y t he 
perce nta ge of patter ns c orrectl y disti n g uis he d fr o m n o vel distract ors.  
6. 2. 6.  
M orris Water Maze Test  
T he M W M test is use d t o assess hi p p oca m pal-de pe n de nt s patial lear ni n g a n d me m or y  (M orris, 1 9 8 4 ).  A  
virt ual -realit y versi o n of M W M test is t o be a d mi nistere d at t he ti me p oi nts s pecifie d i n Ta ble  6 -1 .  
T his tas k is a h u ma n a nal o gue  of t he classic M W M  tas k c o m m o nl y use d i n r o de nt st u dies.  Patie nts were 
t ol d t o na vi gate t hr o u g h a virt ual 3-di me nsi o nal p o ol prese nte d o n t he scree n usi n g a j o ystic k .  T he g oal 
of t he test is t o fi n d a n d re me m ber t he l ocati o n of a hi d de n platf or m, usi n g vis ual c ues place d o n t he 
walls .  Patie nts ha ve  a first-pers o n vie w p oi nt wit h a fiel d of vie w c o m para ble t o t he h u ma n e ye.  


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6. 2. 7.  
P h ysical E xa mi nati o n a n d Vital Si g ns  
P h ysical e xa mi nati o n will i ncl u de a re vie w of all b o d y s yste ms  a n d meas ure me nt of wei g ht , per eac h 
I n vesti gat or’s sta n dar d practice.  P h ysical e xa mi nati o n fi n di n gs will be d oc u me nt e d i n the s u bject’s 
s o urce d oc u me nts.   
Vital si g ns i ncl u de meas ure me nt of bl o o d press ure, p ulse,  res pirat or y rate, a n d b o d y te m perat ure.  
A n y p h ysical e xa mi nati o n fi n di n g or vital si g n mea s ure me nt t hat re prese nts a w orse ni n g fr o m Baseli ne 
c o n diti o n a n d is c o nsi dere d b y t he In vesti gat or t o be cli nicall y si g nifica nt will be rec or de d as a n A E (see 
Secti o n  7 ). 
6. 2. 8.  
1 2 -Lea d Electr ocar di o gra m  
A 1 2 -lea d E C G will be perf or me d usi n g vali date d mac hi ner y a vaila ble l ocall y t o eac h cli nical site.  Eac h 
re p ort will be re vie we d b y t he I n vesti gat or f or q ualifie d s u b-i n vesti gat or a n d assesse d as n or mal, 
a b n or mal –  n ot cli nicall y si g nifica nt, or a b n or mal –  cli nicall y si g nifica nt.  A b n or mal, cli nicall y si g nifica nt 
fi n di n gs t hat re prese nt a w orse ni n g fr o m Baseli ne will be rec or de d as a n A E . 
6. 2. 9.  
Cli nical La b orat or y Assess m e nts 
T w o bl o o d sa m ples will be c ollecte d at t he ti me p oi nts s pecifie d i n Ta ble  6 -1  f or assess me nt of r o uti ne 
c he mistr y a n d he mat ol o g y a nal ytes .   
All sa m ples will be a nal yze d l ocall y.  


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T a ble  6 -2  
Cli nic al L a b or at or y A n al ytes  
Ser u m C he mistr y  
He m at ol o g y  
•  
Al b u mi n  
•  
Al kali ne p h os p hatase  
•  
A L T  
•  
A S T  
•  
Bilir u bi n (t otal a n d direct)  
•  
Gl uc ose  
•  
Calci u m  
•  
T otal c h olester ol  
•  
Tri gl yceri des  
•  
Creati ni ne  
•  
Ga m ma -gl uta m yl tra nsferase  
•  
Lactate de h y dr o ge nase  
•  
P h os p hate  
•  
P otassi u m  
•  
S o di u m  
•  
 
•  
Differe ntial (a bs ol ute a n d perce nt):  
•  
Bas o p hils  
•  
E osi n o p hils  
•  
L y m p h oc ytes  
•  
M o n oc ytes  
•  
Ne utr o p hils  
•  
Er yt hr oc ytes:  
•  
Mea n c or p usc ular he m o gl o bi n  
•  
Mea n c or p u sc ular he m o gl o bi n c o nce ntrati o n 
•  
Mea n c or p usc ular v ol u m e 
•  
He m o gl o bi n  
•  
Le u k oc ytes  
•  
Platelets  
•  
 
Cli nical la b orat or y fi n di n gs t hat re prese nt a w orse ni n g fr o m Baseli ne val ue a n d are c o nsi dere d b y t he 
In vesti gat or t o be cli nicall y si g nifica nt w ill be rec or de d as a n A E (refer t o Secti o n  7 ). 
 
6. 2. 1 0.  
Wit h dra wal of S u bjects  
A s u bject ma y be disc o nti n ue d fr o m st u d y treat me nt at a n y ti me if t he s u bject, t he I n vesti gat or, or t he 
S p o ns or feels t hat it is n ot i n t he s u bjec t’s best i nterest to c o nti n ue .  T he f oll o wi n g is a list of p ossi ble 
reas o ns f or st u d y treat me nt disc o nti n uati o n: 
•  
S u bject wit h dra wal of c o nse nt ( or asse nt)  
•  
S u bject lac ks a bilit y  t o pr o vi de c o nti n ue d i nf or me d c o nse nt ( or asse nt) a n d/ or s o u n d j u d ge me nt 
as t o whet her t o c o nti n ue  i n t he st u d y 
•  
S u bject de vel o p s s uici dal i deati o ns or atte m pts s uici de 
•  
S u bject is n ot c o m plia nt wit h st u d y pr oce d ures  
•  
A E  t hat i n t he o pi ni o n of t he In vesti gat or w o ul d be i n t he best i nterest of t he s u bject t o 
disc o nti n ue st u d y treat me nt  
•  
Pr ot oc ol vi olati o n re q uiri n g disc o nti n uati o n of st u d y treat me nt  


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C o nfi de nti al  
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L ost t o f oll o w -u p  
•  
S p o ns or re q uest f or earl y ter mi nati o n of st u d y  
If a s u bject is wit h dra w n fr o m treat me nt d ue t o a n A E , t he s u bject will be f oll o we d a n d treate d b y t he 
I n vesti gat or u ntil t he a b n or mal para meter or s y m pt o m has res ol ve d or sta bilize d.   
A s u bject ma y be wit h dra w n fr o m t he st u d y at a n y ti me if t he s u bject, t he I n vesti gat or, or t he S p o ns or 
feels t hat it is n ot i n t he s u bject’s best i nterest t o c o nti n ue.   
All s u bjects are free t o wit h dra w fr o m partici pati o n at a n y ti me, f or a n y reas o n, s pecifie d or u ns pecifie d, 
a n d wit h o ut prej u dice.  
Reas o na ble atte m pts will be ma de b y t he I n vesti gat or t o pr o vi de a reas o n f or s u bject wit h dra wals.  T he 
reas o n f or t he s u bject’s wit h dra wal fr o m t he st u d y will be s pecifie d i n t he s u bject’s s o urce d oc u me nts.   
U p t o f o ur s u bjects w h o wit h dra w fr o m t he st u d y treat me nt a n d/ or st u d y  f or a reas o n pri or t o c o m pleti n g 
st u d y assess me nts at Wee k 4 of t he sec o n d treat me nt peri o d  ma y  be re place d.   
Refer t o Ta ble  6 -1  f or assess me nts t o be perf or me d f or s u bjects w h o pre mat urel y disc o nti n ue st u d y dr u g. 


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7.  
A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E 
E V E N T S/ S A F E T Y R E P O R TI N G  
T he I n vesti gat or is res p o nsi ble f or re p orti n g of e ve nts meeti n g t he criteria a n d defi niti o n of a n A E  or S A E 
as pr o vi de d i n t his pr ot oc ol.   
7. 1.  
Defi niti o ns a n d Criteri a  
7. 1. 1.  
A d verse E ve nts  
Per I nter nati o nal C o u ncil f or Har m o nisati o n ( I C H) E 2 A: A n A E is a n y u nt o war d me dical occ urre nce i n a 
patie nt or cli nical i n vesti gati o n s u bject a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot 
necessaril y ha ve t o ha ve a ca usal relati o ns hi p wit h t his treat me nt .  A n A E ca n t heref ore be a n y 
u nfa v ora b le a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or e xa m ple), s y m pt o m, or 
disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d t o 
t he me dici nal pr o d uct.  
Me dical i nter ve nti o ns s uc h as s ur ger ies, dia g n ostic pr oce d ures, a n d t hera pe utic pr oce d ures are n ot A Es 
b ut t he acti o n ta ke n t o treat t he me dical c o n diti o n .  T he y s h o ul d be rec or de d as treat me nt of t he A Es.  
7. 1. 2.  
Seri o us A d verse E ve nts  
A n S A E or reacti o n is a n y u nt o war d me dical occ urre nce t hat at a n y d ose:  
•  
Res ults i n deat h  
•  
Is life-t hreate ni n g  
•  
Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n  
•  
Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y  
•  
Is a c o n ge nital a n o mal y or birt h defect  
•  
Is a n i m p orta nt me dical e ve nt (e. g., i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or 
aller gic br o nc h os pas m; bl o o d d yscrasias, or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; or 
de vel o p me nt of dr u g de pe n de nc y or dr u g a b use; mali g na nc y)  
N ote: T he ter m “life -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he s u bject was 
at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d 
deat h if it were m ore se vere.  
Me dic al a n d scie ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life -
t hreate ni n g or res ult i n deat h or h os pitalizati o n, b ut ma y je o par dize t he s u bject or ma y re q uire 
i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti o n a b o ve.  T hese s h o ul d als o us uall y 
be c o nsi dere d seri o us.  
E xa m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic  
br o nc h os pas m; bl o o d d yscrasias, or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; or de vel o p me nt of 
dr u g de pe n de nc y or dr u g a b use.  


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Seri o us ness ( n ot se verit y) ser ves as a g ui de f or defi ni n g re g ulat or y re p orti n g o bli gati o ns .  A n S A E is n ot 
necessaril y se vere; e. g., a n o ver ni g ht h os pitalizati o n f or a dia g n ostic pr oce d ure m ust be re p orte d as a n 
S A E e ve n t h o u g h t he occ urre nce is n ot me dicall y seri o us .  B y t he sa me t o ke n, a se vere A E is n ot 
necessaril y seri o us: na usea of se veral h o urs’ d urati o n ma y be rate d  as se vere b ut ma y n ot be c o nsi dere d 
seri o us. 
7. 1. 3.  
U ne x pecte d A d verse Dr u g Reacti o ns  
A n u ne x pecte d a d verse dr u g reacti o n ( A D R) is a reacti o n f or w hic h t he nat ure or se verit y is n ot c o nsiste nt 
wit h t he a p plica ble pr o d uct i nf or mati o n (I n vesti gat or’s Br oc h ure, Pa c ka ge I nsert f or mar kete d pr o d ucts) .  
U ntil pr o d uct i nf or mati o n is a me n de d, e x pe dite d re p orti n g is re q uire d f or a d diti o nal occ urre nces of t he 
reacti o n.  Re p orts t hat a d d si g nifica nt i nf or mati o n o n s pecificit y or se verit y of a k n o w n, alrea d y 
d oc u me nte d S A E c o nstit ute u ne x pecte d e ve nts .  F or e xa m ple, a n e ve nt m ore s pecific or m ore se vere t ha n 
descri be d i n t he I n vesti gat or's Br oc h ure w o ul d be c o nsi dere d " u ne x pecte d. ”  S pecific e xa m ples w o ul d be 
(a) ac ute re nal fail ure as a la bele d A D R wit h a s u bse q ue nt ne w re port of i nterstitial ne p hritis a n d ( b) 
he patitis wit h a first re p ort of f ul mi na nt he patitis.  
G ui da nce o n re p orti n g A Es a n d S A Es is descri be d i n Secti o n 7. 2 . 
7. 1. 4.  
A b n or mal La b orat or y Val ues  
A n y a b n or malit y i n a la b orat or y val ue t hat is ne w i n o nset or w hic h has w orse ne d i n se verit y or fre q ue nc y 
fr o m t he baseli ne c o n diti o n a n d meets 1 of t he f oll o wi n g criteria will be rec or de d o n t he A E pa ges of t he 
eC R F:  
•  
Re q uires t hera pe utic i nter ve nti o n or dia g n ostic tests.  
•  
Lea ds t o disc o nti n ua ti o n of i n vesti gati o nal pr o d uct. 
•  
Has acc o m pa n yi n g or i n d uci n g s y m pt o ms or si g ns.  
•  
Is j u d ge d b y t he In vesti gat or as cli nicall y si g nifica nt. 
7. 1. 5.  
Assessi n g I nte nsit y a n d Relati o ns hi p  
All A Es will be assesse d o n 2 descri pti ve para meters: i nte nsit y a n d relati o ns hi p t o t he i n vesti gati o nal 
pr o d uct:  
•  
I nte nsit y refers t o t he se verit y of a n e ve nt a n d refere nces i m pact o n a s u bject’s f u ncti o ni ng.  
•  
Ca usalit y  refers t o t he li keli h o o d t hat t he e ve nt bei n g assesse d was ca use d b y t he i n vesti gati o nal 
pr o d uct.  


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I nte nsit y 
Eac h A E will be classifie d acc or di n g t o t he f oll o wi n g criteria:  
Mil d:  
T he A E d oes n ot i nterfere i n a si g nifica nt ma n ner wit h t he s u bject’s n or mal le vel of 
f u ncti o ni n g. 
M o derate:  
T he A E pr o d uces s o me i m pair me nt of f u ncti o ni n g, b ut is n ot hazar d o us t o t he 
s u bject’s healt h. 
Se vere:  
T he A E pr o d uces si g nifica nt i m pair me nt of f u ncti o ni n g or i nca pacitati o n a n d is a 
defi nite hazar d t o t he s u bject’s healt h. 
W he n c ha n ges i n t he i nte nsit y of a n A E occ ur m ore fre q ue ntl y t ha n o nce a da y, t he ma xi m u m i nte nsit y 
f or t he e x perie nce s h o ul d be n ote d.  If t he i nte nsit y cate g or y c ha n ges o ver a n u m ber of da ys, t h ose 
c ha n ges s h o ul d be rec or de d se paratel y ( wit h disti nct o nset dates).  
C a us alit y  
Eac h A E will be assesse d as t o its relati o ns hi p t o t he i n vesti gati o nal pr o d uct, base d o n t he f oll o wi n g 
criteria.  T he ca usalit y assess me nt of a n A E t o t he  i n vesti gati o nal pr o d uct will be rate d as f oll o ws b y t he 
i n vesti gat or: 
N ot relate d:  
N o ca usal relati o ns hi p e xists bet wee n t he i n vesti gati o nal pr o d uct a n d t he A E, b ut a n 
o b vi o us alter nati ve ca use e xists, e. g., t he s u bject’s u n derl yi n g me dical c o n diti o n or 
co nc o mita nt t hera p y.  
P ossi bl y relate d:  
A c o n necti o n wit h t he a d mi nistrati o n of t he i n vesti gati o nal pr o d uct a p pears u nli kel y, 
b ut ca n n ot be r ule d o ut wit h certai nt y .  A n A E ma y be c o nsi dere d p ossi bl y relate d if 
or w he n it meets 2 of t he f oll o wi n g criteria: ( 1) it f oll o ws a reas o na ble te m p oral 
se q ue nce fr o m a d mi nistrati o n of t he i n vesti gati o nal pr o d uct; ( 2) it c o ul d n ot rea dil y 
ha ve bee n pr o d uce d b y t he s u bject’s cli nical state, e n vir o n me ntal or t o xic fact ors, or 
ot her m o des of t hera p y a d mi nistere d t o t he s u bject; or ( 3) it f oll o ws a k n o w n patter n 
of res p o nse t o t he i n vesti gati o nal pr o d uct.  
Relate d:  
T here is at least a reas o na ble p ossi bilit y of a ca usal relati o ns hi p bet wee n t he A E a n d 
t he i n vesti gati o nal pr o d uct. T his mea ns t hat t here are facts (e vi de nce) or arg u me nts t o 
s u g gest a ca usal relati o ns hi p. 
W he n assessi n g t he relati o ns hi p t o t he i n vesti gati o nal pr o d uct, t he f oll o wi n g criteria will be c o nsi dere d:  
•  
P ositi ve rec halle n ge  
•  
P ositi ve dec halle n ge (res ol uti o n u p o n st o p pi n g s us pect t he i n vesti gati o nal pr o d uct, i n  a bse nce of 
ot her i nter ve nti o n or treat me nt)  
•  
K n o w n class effect  
•  
Bi ol o gical pla usi bilit y  
•  
Lac k of alter nati ve e x pla nati o n — c o nc o mita nt dr u g or disease  


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7. 2.  
Re p orti n g Pr oce d ures a n d Re q uire me nts  
7. 2. 1.  
A d verse E ve nts  
A E s occ urri n g fr o m w he n t he s u bject si g ns t he i nf or me d c o nse nt f or m (I C F)  u ntil t he last st u d y e ve nt will 
be rec or de d .  A n y A Es occ urri n g bef ore t he start of treat me nt ( i.e., bef ore t he first d ose of t he 
i n vesti gati o nal pr o d uct)” will be rec or de d i n t he me dical hist or y.  Als o, t he si g n, s y m pt o m, or disease 
pre se nt bef ore starti n g t he treat me nt peri o d are o nl y c o nsi dere d A Es if t he y w orse n after starti n g t he 
treat me nt peri o d. 
If In vesti gat or detects a n A E i n a st u d y s u bject after t he last sc he d ule d f oll o w -u p visit a n d c o nsi ders t he 
e ve nt p ossi bl y relate d or rela te d t o pri or st u d y treat me nt, t he I n vesti gat or s h o ul d re p ort it t o V oisi n 
C o ns ulti n g Life Scie nces .   
T he I n vesti gat or s h o ul d re p ort all A Es o n t he A E pa ge(s) of t he eC R F  a n d s o urce d oc u me nts, re gar dless 
of seri o us ness, se verit y, a n d ca usalit y .  W he ne ver p ossi ble, a n A E will be re p orte d usi n g a dia g n ostic 
ter m, (e. g., “c o m m o n c ol d” or “ u p per res pirat or y i nfecti o n” rat her t ha n “r u n n y n ose, c o u g h, mil d fe ver”) 
a n d s h o ul d be descri be d wit h t he attri b utes descri be d i n Secti o n 7. 1. 5 . 
A n y st u d y -relate d A Es t hat are o n g oi n g at t he F oll o w-u p visit s h o ul d be f oll o we d u ntil res ol ve d.  
 
7. 2. 2.  
Seri o us A d verse E ve nts  
Eac h A E will be ass esse d t o deter mi ne w het her it meets seri o us ness criteria ( Secti o n  7. 1. 2 ).  If t he A E is 
c o nsi dere d seri o us, t he I n vesti gat or s h o ul d re p ort t his e vent t o  V oisi n C o ns ulti n g Life Scie nce s o utli ne d 
bel o w a n d als o t o t he I E C acc or di n g t o its sta n dar d o perati n g pr oce d ures.  
If t he I n vesti gat or detects a n S A E i n a st u d y s u bject after t he last sc he d ule d f oll o w -u p visit, a n d c o nsi ders 
t he S A E relate d or p ossi bl y relate d t o pri or st u d y treat me nt, t he I n vesti gat or s h o ul d re p ort it t o V ois in 
C o ns ulti n g  Life Scie nces . 
S A E Re p orti n g:  
E -m ail :  ei psafet y @ v oisi nc o ns ulti n g.c o m  
All i nf or mati o n a b o ut S A Es will be c ollecte d a n d re p orte d via t he S A E f or m a n d se nt b y e -mail messa ge  
a ut o maticall y t hr o u g h t he e C R F or ma n uall y i n case t he s yste m is d o w n.  T he I n vesti gat or s h o ul d se n d 
t he i nitial re p ort wit hi n 2 4 h o urs of bec o mi n g a ware of t he S A E.  At mi ni m u m, t he i nitia l re p ort s h o ul d 
i ncl u de t he f oll o wi n g i nf or mati o n: 
•  
E ve nt  
•  
St u d y c o de  
•  
S u bject  n u m ber, i nitials, a n d date of birt h  
•  
I n vesti gati o nal pr o d uct 
•  
Re p orter na me a n d c o ntact i nf or mati o n  
I n t he case of a “ mi ni m u m re p ort” ( o ne t hat s olel y c o m prises t he i nf or mati o n b ullete d a b o ve), a m ore 
detaile d f oll o w -u p re p ort s h o ul d be se nt as s o o n as m ore i nf or mati o n bec o mes a vaila ble b ut n o later t ha n 


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7 cale n dar da ys after t he date of t he i nitial re p ort .  Eac h S A E s h o ul d be f oll o we d u p u ntil res ol uti o n or 
sta bilizati o n a n d f or re p orte d deat hs, t he I n vesti gat or s h o ul d s u p pl y V oisi n C o ns ulti n g Life Scie nces  a n d 
t he I E C wit h a n y a d diti o nal re q ueste d i nf or mati o n (e. g., a ut o ps y re p orts a n d ter mi nal me dical re p orts). 
If a n S A E f or m is use d, t he ori gi nal S A E f or m s h o ul d be  si g ne d a n d ke pt at t he st u d y site .  T he S p o ns or  
or its desi g nee  will be res p o nsi ble f or deter mi ni n g a n d i n t ur n, re p orti n g S A Es t o re g ulat or y a ut h orities 
acc or di n g t o t he a p plica ble re g ulat or y re q uire me nts.  
S A E s t hat are o n g oi n g at t he F oll o w-u p visit s h o ul d be f oll o we d u ntil res ol ve d.  


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D A T A M A N A G E M E N T A N D S T A TI S TI C A L A N A L Y SI S  
8. 1.  
D at a M a n a ge me nt a n d Q u alit y Ass ur a nce C o nsi der ati o ns  
T his st u d y will e m pl o y  eC R Fs .  T he site will be trai ne d o n  s pecific f or ms a n d pr oce d ures f or s o urce 
d oc u me ntati o n a n d mai nte na nce of a n a u dit trail of t he data t hat is e ntere d in t he eC R F pri or t o st u d y 
i nitiati o n. 
St u d y pers o n nel at eac h site will e nter data fr o m s o urce d oc u me nts c orres p o n di n g t o a s u bject’s visit int o 
t he pr ot oc ol-s pecific eC R F  w he n t he i nf or mati o n c orres p o n di n g t o t hat visit is a vaila ble .  S u bjects will 
n ot be i de ntifie d b y na me  o n t he eC R F pa ges,  i n t he st u d y data base or o n a n y st u d y d oc u me nts t o be 
c ollecte d b y t he S p o ns or ( or desi g nee), b ut will be i de ntif ie d b y s u bject n u m ber ( 6 di gits: t he first 3  f or 
t he i nstit uti o n a n d t he last 3  f or t he s u bject). 
T he I n vesti gat or s will pre pare a n d mai ntai n a de q uate a n d acc urate s o urce d oc u me nts desi g ne d t o rec or d 
all o bser vati o ns a n d ot her perti ne nt data f or eac h s u bje ct treate d wit h t he st u d y dr u g.  
If a c orrecti o n is re q uire d f or a eC R F, t he  ti me a n d date will be rec or de d b y t he pers o n u p dati n g eC R F 
data t o create a n a u dit trail .  T he I n vesti gat or is res p o nsi ble f or all i nf or mati o n c ollecte d o n s u bjects 
e nr olle d i n t hi s st u d y.  All data c ollecte d d uri n g t he c o urse of t his st u d y m ust be re vie we d a n d verifie d f or 
c o m plete ness a n d acc urac y b y t he I n vesti gat or.  
Q ueries will be iss ue d f or a n y i nc o nsiste ncies, o missi o ns, a n d discre pa ncies a n d will be res ol ve d b y t he 
a p pr o priate parties.  
Data base l oc k will occ ur o nce q ualit y ass ura nce pr oce d ures ha ve bee n c o m plete d.  
T he statistical a nal ysis of t hese data will be pe rf or me d b y t he S p o ns or or  desi g nee .  All A Es will be c o de d 
usi n g t he latest versi o n of t he Me dical Dicti o nar y f or Re g ulate d Acti vities ( Me d D R A) .  F urt her details f or 
t he pla n ne d statistical a nal yses will be prese nte d i n a se parate statistical a nal ysis pla n t o be fi nalize d pri or 
t o t he e n d of e nr oll me nt. 
All pr oce d ures f or t he ha n dli n g a n d a nal ysis of data will be c o n d ucte d usi n g g o o d c o m p uti n g practices 
meeti n g U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A ), E ur o pea n Me dici nes A ge nc y, a n d I C H 
g ui deli nes f or t he ha n dli n g a n d a nal ysis of data f or cli nical st u dies.  Data ma na ge me nt details will be 
o utli ne d i n a se parate data ma na ge me nt pla n.  
8. 2.  
S a m ple Size  
N o f or mal sa m ple size calc ulati o n was perf or me d.  A sa m ple size of 1 6 s u bjects is c o nsi dere d a p pr o priate 
f or deter mi nati o n of t he preli mi nar y safet y a n d t olera bilit y of nefla ma pi m o d i n t his s u bject p o p ulati o n.  
8. 3.  
A n al ysis Sets  
T he safet y a nal ysis set will i ncl u de a n y s u bject w h o recei ves at least 1  d ose of st u d y dr u g.  
T he efficac y a nal ysis set will i ncl u de a n y s u bject w h o recei ves at least 1  d ose of st u d y dr u g a n d at least 
o ne p ost d ose assess me nt o n t he C A N T A B batter y a n d/ or M W M . 


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S afet y  
T he i nci de nce of treat me nt -e mer ge nt A E a n d S A Es , t he ca usal relati o ns hi p bet wee n a n A E/ S A E a n d t he 
St u d y Dr u g , a n d se verit y will be ta b ulate d b y treat me nt ( d ose) gr o u p.  
I n di vi d ual cli nicall y-si g nifica nt c ha n ges i n cli nical la b orat or y a n d E C G para meters will be liste d al o n g 
wit h me dia n a n d mea n a n d sta n dar d de viati o n b y treat me n t gr o u p.   
8. 5.  
Effic ac y  
T he efficac y varia bles are : 
•  
Late nc y d uri n g t he lear ni n g p hase of virt ual M W M ( hi d de n platf or m trai ni n g) d uri n g t he 
nefla ma pi m o d -treat me nt peri o d c o m pare d t o t hat d uri n g t he place b o-a d mi nistrati o n 
peri o d.  
•  
Perce nt of ti me s pe nt i n t he c or rect q ua dra nt d uri n g M W M pr o be test d uri n g t he 
nefla ma pi m o d -treat me nt peri o d c o m pare d t o t hat d uri n g t he place b o-a d mi nistrati o n 
peri o d.  
•  
N u m ber of o verall err ors i n t he C A N T A B paire d ass ociates lear ni n g tas k d uri n g t he 
nefla ma pi m o d -treat me nt peri o d c o m pare d t o t hat d uri n g t he place b o-a d mi nistrati o n 
peri o d.  
8. 6.  
I nteri m A n al ysis 
N o i nteri m a nal ysis is pla n ne d.   


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9.  
S T U D Y M A N A G E M E N T  
9. 1.  
Et hics a n d C o nse nt  
9. 1. 1.  
Re g ulati o ns a n d G ui deli nes  
T he st u d y will be perf or me d i n acc or da nce wit h t his pr ot oc ol,  U nite d States  I n vesti gati o nal Ne w 
Dr u g A p plicati o n  re g ulati o ns ( 2 1 C F R 3 1 2), E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, l ocal nati o nal la ws (as 
a p plica ble)  a n d I C H g ui deli nes f or G o o d Cli nical Practice .   
9. 1. 2.  
I n de pe n de nt Et hics C o m mittee 
C o n d uct of t he st u d y m ust be a p pr o ve d b y a n a p pr o priatel y c o nstit ute d I E C .  A p pr o val is re q uire d f or t he 
st u d y pr ot oc ol, i n vesti gati o nal dr u g br oc h ure, pr ot oc ol a me n d me nts, I C Fs, s u bject i nf or mati o n s heets, 
a n d a d vertisi n g materials .  N o i n vesti gati o nal pr o d uct will be s hi p pe d t o a site u ntil writte n I E C 
a ut h orizati o n has bee n recei ve d b y t he S p o ns or  or its desi g nee . 
9. 1. 3.  
I nf or me d C o nse nt 
F or eac h st u d y  s u bject, a writte n I C F will be o btai ne d bef ore a n y pr ot oc ol-relate d acti vities.  As part of 
t his pr oce d ure, t he I n vesti gat or or a desi g nate d re prese ntati v e m ust e x plai n orall y a n d i n writi n g t he 
nat ure, d urati o n, a n d p ur p ose of t he st u d y, a n d t he acti o n of t he i n vesti gati o nal pr o d uct i n s uc h a ma n ner 
t hat t he s u bject a n d (if a p plica ble) a p p oi nte d g uar dia n are a ware of t he p ote ntial ris ks, i nc o n ve nie nces, or  
a d verse effects t hat ma y occ ur .  S u bject s s h o ul d be i nf or me d t hat t he y ma y wit h dra w fr o m t he st u d y at 
a n y ti me.  T he y will recei ve all i nf or mati o n t hat is re q uire d b y l ocal re g ulati o ns a n d I C H g ui deli nes .  T he 
In vesti gat or or a desi g nate d re prese ntati ve w ill pr o vi de t he S p o ns or  or its desi g nee  wit h a c o p y of t he 
I E C-a p pr o ve d I C F bef ore t he start of t he st u d y.  
9. 2.  
I n de m nific ati o n 
T he S p o ns or ’s i n de m nificati o n of t he I n vesti gat or a n d i nstit uti o n d uri n g t he c o n d uct of t his st u d y is 
a d dresse d i n a letter of i n de m n ificati o n pr o vi de d as a se parate d oc u me nt.  Ot her i n de m nificati o n or 
i ns ura nce will be pr o vi de d as necessar y u n der l ocal re g ulati o ns. 
9. 3.  
Disc o nti n u ati o n of t he St u d y b y t he S p o ns or  
T he pla n ne d st u d y peri o d is a p pr o xi matel y 1. 5  years , u ntil t he last visit of t he last s u bject (i ncl u di n g t he 
f oll o w-u p visit) .  T he pla n ne d s u bject partici pati o n is a p pr o xi matel y 3 5  wee ks, i ncl u di n g 2 0  wee ks of 
treat me nt.  O nce t he s u bjects ha ve e n de d t heir partici pati o n i n t he st u d y, t he y will ret ur n t o t heir sta n dar d 
of care treat me nt as deter mi ne d b y t heir p h ysicia n.  
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he st u d y at t his site or at m ulti ple sites f or safet y or 
a d mi nistrati ve reas o ns at a n y t i me.  If t he S p o ns or or I n vesti gat or disc o vers c o n diti o ns arisi n g d uri n g 
t he st u d y t hat s u g gest t he st u d y s h o ul d be halte d, t he n t his ca n ha p pe n o nl y after a p pr o priate c o ns ultati o n 
bet wee n t he S p o ns or a n d I n vesti gat or .  C o n diti o ns t hat ma y warra nt st u d y te r mi nati o n i ncl u de, b ut are n ot 
li mite d t o: 
•  
T he disc o ver y of a n y u ne x pecte d, si g nifica nt, or u nacce pta ble ris k t o t he s u bjects e nr olle d i n t he 
st u d y. 
•  
Fail ure of t he I n vesti gat or t o e nter s u bjects at a n acce pta ble rate. 


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•  
U nsatisfact or y s u bject e nr oll me nt  wit h  res pect  t o  q ualit y  a n d/ or  q ua ntit y  or  data  rec or di n g  is 
i nacc urate a n d/ or i nc o m plete o n a c hr o nic basis. 
•  
I ns ufficie nt a d here nce t o t he pr ot oc ol re q uire me nts. 
•  
A decisi o n o n t he part of t he S p o ns or t o s us pe n d or disc o nti n ue de vel o p me nt of st u d y d r u g. 
S h o ul d  t he st u d y be ter mi nate d a n d/ or t he site cl ose d f or w hate ver reas o n, all d oc u me ntati o n a n d 
i n vesti gati o nal pr o d uct pertai ni n g t o t he st u d y m ust be ret ur ne d t o t he S p o ns or  or its desi g nee . 
9. 4.  
St u d y D oc u me nt ati o n  
B y si g ni n g a c o p y of F or m F D A 1 5 7 2 or ot her c o u n tr y-s pecific re g ulat or y f or ms, t he In vesti gat or 
ac k n o wle d ges t hat he/s he has recei ve d a c o p y of t he i n vesti gat or’s br oc h ure o n n efla ma pi m o d  a n d ass ures 
t he S p o ns or t hat he/s he will c o m pl y wit h t he pr ot oc ol a n d t he pr o visi o ns state d i n F or m F D A 1 5 7 2 a n d 
ot h er c o u ntr y-s pecific f or ms.  N o c ha n ges i n t his pr ot oc ol ca n be ma de wit h o ut t he S p o ns or’s writte n 
a p pr o val. 
9. 5.  
St u d y M o nit ori n g a n d A u diti n g  
T his st u d y will be m o nit ore d f or q ualit y ass ura nce at all sta ges of its de vel o p me nt b y t he cli nical researc h 
pers o n nel e m pl o ye d b y t he S p o ns or  or its desi g nee .  M o nit ori n g will i ncl u de pers o nal visits , 
ce ntral/re m ote e C R F re vie w,  a n d tele p h o ne c o m m u nicati o n t o ass ure t hat t he i n vesti gati o n is c o n d ucte d 
acc or di n g t o t he pr ot oc ol, sta n dar d o perati n g pr oce d ures, G ui deli nes of G o o d Cli nical Practice, a n d 
a p plica ble re g ulat or y re q uire me nts .  Q ualit y c o ntr ol pr oce d ures will be a p plie d t o eac h sta ge of data 
ha n dli n g t o e ns ure t hat all data are relia ble a n d ha ve bee n pr ocesse d c orrectl y .  O n -site re vie w of eC R Fs 
will i ncl u de a re vie w of f or ms f or c o m plete ness a n d clarit y, a n d c o nsiste nc y wit h s o urce d oc u me nts 
a vaila ble f or eac h s u bject.   
9. 6.  
Use of St u d y Fi n di n gs  
B y s i g ni n g t he st u d y pr ot oc ol, t he I n vesti gat or a grees t o t he use of res ults of t he st u d y f or t he p ur p oses of 
nati o nal a n d i nter nati o nal re gistrati o n .  If necessar y, t he a ut h orities will be n otifie d of t he I n vesti gat or’s 
na me, a d dress, q ualificati o ns, a n d e xte nt of i n v ol ve me nt .  Re p orts c o veri n g cli nical a n d bi o metric as pects 
of t he st u d y will be pre pare d b y t he S p o ns or or its desi g nee . 
9. 7.  
P u blic ati o ns  
T he cli nical st u d y will be re gis tere d at 3 8 Tw w w.cli nicaltrials. g o v
3 8 T a n d 
3 8 Tw w w.cli nicaltrialsre gister.e u
3 8 T.  T he 
pre parati o n a n d s u b mittal f or p u blicati o n of ma n uscri pts c o ntai ni n g t he st u d y res ults s hall be i n 
acc or da nce wit h a pr ocess deter mi ne d b y m ut ual writte n a gree me nt a m o n g t he st u d y S p o ns or a n d 
partici pati n g i nstit uti o ns .  T he p u blicati o n or prese ntati o n of a n y st u d y res ults s hall c o m pl y wit h all 
a p plica ble pri vac y la ws.  
9. 8.  
Rec or di n g, Access a n d Rete nti o n of S o urce D at a  
T he I n vesti gat or s m ust ma ke st u d y  data accessi ble t o t he m o nit or, ot her a ut h orize d re prese ntati ves of t he 
S p o ns or ( or desi g nee ) a n d Re g ulat or y A ge nc y i ns pectors u p o n re q uest.  


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A file f or eac h s u bject m ust be mai ntai ne d t hat i ncl u des t he si g ne d I nf or me d C o nse nt a n d c o pies of all 
s o urce d oc ume ntati o n relate d t o t hat s u bject .  T he I n vesti gat or m ust e ns ure t he relia bilit y a n d a vaila bilit y 
of s o urce d oc u me nts fr o m w hic h t he i nf or mati o n o n t he eC R F was deri ve d.  
All  st u d y  d oc u me nts  ( s u bject files,  si g ne d I C Fs, S t u d y  File  N ote b o o k,  etc.)  m ust  be  kept  sec ure d  f or  a 
peri o d of t w o years f oll o wi n g mar keti n g of t he i n vesti gati o nal pr o d uct .  T here ma y be ot her circ u msta nces 
f or w hic h t he S p o ns or is re q uire d t o mai ntai n st u d y rec or ds a n d, t heref ore, t he S p o ns or s h o ul d be c o ntacte d 
pri or t o re m o vi n g st u d y rec or ds f or a n y reas o n. 
9. 9.  
Pr ot oc ol Vi ol ati o ns  
A pr ot oc ol vi olati o n occ urs w he n t he s u bject, I n vesti gat or, or S p o ns or fails t o a d here t o si g nifica nt 
pr ot oc ol re q uire me nts affecti n g t he i ncl usi o n, e xcl usi o n, s u bject safet y, a n d pri mar y e n d p oi nt criteria .  
Pr ot oc ol vi olati o ns f or t his st u d y i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  
Fail ure t o meet i ncl usi o n/e xcl usi o n criteria  
•  
Use of a pr o hi bite d c o nc o mita nt me dicati o n  
Fail ure t o c o m pl y wit h G o o d Cli nical Practice g ui deli nes will als o res ult i n a pr ot oc ol vi olati o n .  T he 
S p o ns or will deter mi ne if a pr ot oc ol vi olati o n will res ult i n wit h dra wal of a s u bject.  
W he n a pr ot oc ol vi olati o n occ urs, it will be disc usse d wit h t he I n vesti gat or a n d a Pr ot oc ol Vi olati o n F or m 
detaili n g t he vi olati o n will be ge nerate d .  T his f or m will be si g ne d b y a S p o ns or re prese ntati ve a n d t he 
I n vesti gat or.  A c o p y of t he f or m will be fi le d i n t he site’s re g ulat or y bi n der a n d i n t he S p o ns or’s files.  


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1 0.  
R E F E R E N C E S  
Ala m & Sc he per.  Tar geti n g ne ur o nal M A P K 1 4/ p 3 8 α acti vit y t o m o d ulate a ut o p ha g y i n t he Alz hei mer 
disease brai n.  A ut o p h a gy  2 0 1 6; 1 2( 1 2): 2 5 1 6 -2 5 2 0.  
Ala m J. Selecti ve Brai n -Tar gete d A n ta g o nis m of p 3 8 M A P K α re d uces hi p p oca m pal I L-1 β Le vels a n d 
i m pr o ves M orris Water Maze  perf or ma nce i n a ge d rats .  J Alz hei mers Dis  2 0 1 5; 4 8( 1): 2 1 9 -2 7.  
Ar ni n g L et al. A S K 1 a n d M A P 2 K 6 as m o difiers of a ge at o nset i n H u nti n gt o n's disease. J M ol Me d 
( Berl) 2 0 0 8 ; 8 6( 4): 4 8 5-9 0.  
Ba d dele y  A D & Hitc h  G.  W or ki n g me m or y.  Psyc h ol Le ar n M otiv  1 9 7 4; 8 4 7 -8 9.  
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Ne ur osci  2 0 1 4; 1 2 8( 4) : 5 2 3-3 6.  
C olié S et al.  Ne ur o nal p 3 8al p ha me diates s y na ptic a n d c o g niti ve d ysf u ncti o n i n a n Alz hei mer's m o use 
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Ne ur oc he m  2 0 1 4; 1 3 0( 1): 1 4 5 -5 9.  
H u nti n gt o n St u d y Gr o u p.  U nifie d H u nti n gt o n’s Dise ase Rati n g Scale: relia bilit y a n d c o nsiste nc y.  M ov 
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Lee J H  et al. Rei nstati n g a berra nt m T O R C1 acti vit y i n H u nti n gt o n's disease mice i m pr o ves disease 
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L y nc h M A.  A ge -relate d ne ur oi nfla m mat or y c ha n ges ne gati vel y i m pact o n ne ur o nal f u ncti o n.  Fr o nt 
A gi n g Ne ur osci 2 0 1 0; 1: 6.  
Mil ner w o o d  AJ, Ra y m o n d L A. Earl y s y na ptic pat h o p h ysi ol o g y i n ne ur o de ge nerati o n: i nsi g hts fr o m 
H u nti n gt o n's disease. Tre n ds Ne ur osci  2 0 1 0; 3 3( 1 1): 5 1 3 -2 3.  
M orris R. De vel o p me nts of a water -maze pr oce d ure f or st u d yi n g s patial lear ni n g i n t he rat. J Ne ur osci 
Met h o ds  1 9 8 4; 1 1: 4 7 – 6 0 . 
O we n et al.  Vis u o -s patial s h ort-ter m rec o g niti o n me m or y a n d lear ni n g after te m p oral l o be e xcisi o ns, 
fr o ntal l o be e xcisi o ns or a m y g dal o-hi p p oca m pect o m y i n ma n.  Ne ur o psyc h ol o gi a  1 9 9 5; 3 3( 1): 1 -2 4.  
P os ner K et al. T he C ol u m bia -S uici de Se verit y Rati n g Scale: i nitial vali dit y a n d i nter nal c o nsiste nc y 
fi n di n gs fr o m t hree m ultisite st u dies wit h a d olesce nts a n d a d ults. A m J Psyc hi atry  2 0 1 1; 1 6 8: 1 2 6 6 -1 2 7 7.  
Priet o et al.  S y na pse -s pecific I L-1 rece pt or s u b u n it rec o nfi g urati o n a u g me nts v ul nera bilit y t o I L-1 β i n t he 
a ge d hi p p oca m p us.   Pr oc N atl Ac a d Sci U S A  2 0 1 5; 1 1 2( 3 6): E 5 0 7 8 -8 7.  
R o y et al.  Tar geti n g h u ma n ce ntral ner v o us s yste m pr otei n ki nases: A n is of or m selecti ve p 3 8 α M A P K 
i n hi bit or t hat atte n uates disease pr o gressi o n i n Alz hei mer's disease m o use m o dels.  A C S C he m Ne ur osci  
2 0 1 5; 6( 4): 6 6 6 -8 0.  
Sa n ders o n et al.  Hi p p oca m pal meta b otr o pic gl uta mate rece pt or l o n g -ter m de pressi o n i n healt h a n d 
disease: f oc us  o n mit o ge n -acti vate d pr otei n ki nase pat h wa ys.  J Ne ur oc he m  2 0 1 6; 1 3 9 S u p pl 2: 2 0 0 -2 1 4.  
S mit h G A et al. Pr o gressi ve a x o nal tra ns p ort a n d s y na ptic pr otei n c ha n ges c orrelate wit h be ha vi oral a n d 
ne ur o pat h ol o gical a b n or malities i n t he heter oz y g o us Q 1 7 5 KI m o use m o del of H u nti n gt o n's disease.  H u m 
M ol Ge net  2 0 1 4; 2 3( 1 7): 4 5 1 0 -2 7.  
S mit h PJ  et al. A c o m paris o n of t he Ca m bri d ge A ut o mate d Ne ur o ps yc h ol o gical Test Batter y ( C A N T A B) 
wit h "tra diti o nal" ne ur o ps yc h ol o gical testi n g i nstr u me nts. J Cli n Ex p Ne ur o psyc h ol  2 0 1 3; 3 5( 3): 3 1 9 -2 8.  
Stei nert J R et al. Ra b 1 1 resc ues s y na ptic d ysf u n cti o n a n d be ha vi o ural deficits i n a Dr os o p hila m o del of 
H u nti n gt o n's disease.  H u m M ol Ge net  2 0 1 2; 2 1( 1 3): 2 9 1 2 -2 2.  
Ta yl or D M  et al. M A P ki nase p h os p hatase 1 ( M K P -1/ D U S P 1) is ne ur o pr otecti ve i n H u nti n gt o n's disease 
via a d diti ve effects of J N K a n d p 3 8 i n hi bit i o n. J Ne ur osci  2 0 1; 3 3( 6): 2 3 1 3 -2 5.  
Tsiri g otis M et al. Acti vati o n of p 3 8 M A P K c o ntri b utes t o e x pa n de d p ol y gl uta mi nei n d uce d  c yt ot o xicit y. 
P L o S O ne  2 0 0 8; 3( 5):e 2 1 3 0.  
Vale ncia A et al.  Striatal s y na pt os o mes fr o m H d h 1 4 0 Q/ 1 4 0 Q k n oc k -i n mice ha ve altere d pr otei n le vels, 
n o vel sites of met hi o ni ne o xi dati o n, a n d e xcess gl uta mate release after sti m ulati o n.  J H u nti n gt o ns Dis  
2 0 1 3; 2( 4): 4 5 9 -7 5.  
Watters o n et al.  De vel o p me nt of n o vel i n vi v o c he mical pr o bes t o a d dress C N S  pr otei n ki nase 
i n v ol ve me nt i n s y na ptic d ysf u nctio n .  P L o S O ne  2 0 1 3; 8( 6):e 6 6 2 2 6.  
X u Q  et al. S y na ptic m uta nt h u nti n gti n i n hi bits s y na psi n -1 p h os p h or ylati o n a n d ca uses ne ur ol o gical 
s y m pt o ms. J Cell Bi ol 2 0 1 3 3 0; 2 0 2( 7): 1 1 2 3 -3 8.  


EI P 1 9 -N F D -4 0 1, Versi o n 3. 0, 3 0  J uly, 2 0 1 9 
P a ge 5 0  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
Y ue n E Y  et al. Disr u pte d G A B A A R traffic ki n g a n d s y na ptic i n hi biti o n i n a m o use m o del of H u nti n gt o n's 
disease. Ne ur o bi ol Dis  2 0 1 2; 4 6( 2): 4 9 7 -5 0 2.   
Zi g m o n d A S, S nait h R P. T he h os pital a n xiet y a n d de pressi o n scale.  Act a Psyc hi atr Sc a n d  
1 9 8 3; 6 7( 6): 3 6 1 -7 0.  
 

SAP_001.pdf: 
EI P P har m a, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol # EI P 1 9- N F D - 4 0 1   
  
  
  
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
1 
 
 
  
 
 
 
S T A TI S TI C A L A N A L Y SI S P L A N  
F O R P R O T O C O L EI P 1 9- N F D - 4 0 1 
 
V E R SI O N: 1 
D A T E  O F P L A N:  
F E B 3 , 2 02 0  
 
 
S T U D Y D R U G:  
Nefl a m a pi m o d  
P R O T O C O L N U M B E R: 
EI P 1 9- N F D - 4 0 1 
S T U D Y TI T L E: 
A D o u ble- Bli n d, Pl ace b o- C o ntr olle d T w o- Peri o d 1 0- Week Tre at me nt Wit hi n- S u bject Cr oss over 
St u dy Of C o g nitive Effects Of Nefl a m a pi m o d i n E arly- St a ge H u nti n gt o n Dise ase ( H D)  
S P O N S O R:  
EI P P h ar m a, I nc. 
2 0 1 Br o a d w ay, S uite 2 0 1 
C a m bri d ge M A 0 2 1 3 9 U S A 
 
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n. A n y use, distri b uti o n, or discl os ure wit h o ut t he 
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EI P P har m a, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol # EI P 1 9- N F D - 4 0 1   
  
  
  
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
3 
 
 
  
 
T A B L E O F C O N T E N T S 
1.  
LI S T O F A B B R E VI A TI O N S ....................................................................................... 7 
2.  
I N T R O D U C TI O N ........................................................................................................ 9 
3.  
S T U D Y O BJ E C TI V E S .............................................................................................. 1 0  
3. 1.  
Pri mar y O bjecti ve ....................................................................................................... 1 0  
3. 2.  
Sec o n dar y O bj ecti ves ................................................................................................. 1 0  
3. 3.  
E x pl orat or y Effi cac y a n d Safet y O bjecti ves ............................................................... 1 0  
4.  
S T U D Y D E SI G N ....................................................................................................... 1 1  
4. 1.  
Sa m ple Size J ustificati o n ............................................................................................ 1 1  
4. 2.  
St u d y d urati o n a n d visit sc he d ule ............................................................................... 1 1  
5.  
C LI NI C A L A S S E S S M E N T S ..................................................................................... 1 4  
5. 1.  
Baseli ne a n d Diseas e C haract eristics .......................................................................... 1 4  
5. 2.  
Efficac y Assess me nts ................................................................................................. 1 4  
5. 2. 1.  
M orris Water M aze Test ............................................................................................. 1 4  
5. 2. 2.  
C A N T A B  .................................................................................................................... 1 4 
5. 3.  
Ot her Cli nical Assess me nts ........................................................................................ 1 6  
5. 3. 1.  
C ol u m bia- S uici de Se verit y Rati n g Scale .................................................................... 1 6  
5. 3. 2.  
H os pital A n xiet y a n d De pressi o n Scale ..................................................................... 1 6  
5. 3. 3.  
U nifie d H u nti n gt o n's Disease Rati n g Scale ................................................................ 1 6  
5. 4.  
P h ysical E xa mi nati o n a n d Vital Si g ns ........................................................................ 1 7  
5. 5.  
1 2- Lea d Electr ocar di o gr a m ........................................................................................ 1 8  
5. 6.  
Cli nical La b orat or y Assess me nt ................................................................................. 1 8  
6.  
D E FI NI TI O N S, C O N V E N TI O N S A N D D E RI V E D V A RI A B L E S ......................... 2 0  
6. 1.  
Defi niti o ns a n d c o n ve nti o ns ....................................................................................... 2 0  
6. 2.  
Deri ve d V aria bles ....................................................................................................... 2 1  
6. 2. 1.  
C ha n ge fr o m Baseli ne at eac h treat me nt peri o d ......................................................... 2 1  
6. 2. 2.  
Treat me nt Differ e nce of C ha n ge fr o m Baseli ne wit hi n S u bject Bet wee n 
Peri o ds ........................................................................................................................ 2 1  
7.  
A N A L Y SI S P O P U L A TI O N S .................................................................................... 2 2  
7. 1.  
Safet y P o p ulati o n ........................................................................................................ 2 2  
7. 2.  
E val ua ble Efficac y P o p ul ati o n ( E E P) P o p ulati o n ...................................................... 2 2  
7. 3.  
C o m pleter P o p ulati o n ................................................................................................. 2 2  
8.  
D A T A M A N G E M E N T, R E VI E W A N D P R E E S E N T A TI O N .................................. 2 3  


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8. 1.  
Data Ma na g e me nt a n d Q ualit y Ass ura nce C o nsi derati o ns ......................................... 2 3  
8. 2.  
Data Prese nt ati o n ........................................................................................................ 2 3  
8. 3.  
I nteri m Data Re vie w ................................................................................................... 2 4 
9.  
S T A TI S T SI C A L M E T H O D O L O G Y ......................................................................... 2 5  
9. 1.  
Ge ner al Statistical Met h o d ol o g y ................................................................................ 2 5  
9. 2.  
Prese ntati o n of Effi cac y Meas ures ............................................................................. 2 5  
9. 3.  
S u bject Dis p ositi o n ..................................................................................................... 2 6  
9. 4.  
Pr ot oc ol De viati o ns .................................................................................................... 2 6  
9. 5.  
Missi n g Val ues ........................................................................................................... 2 6  
9. 6.  
S u b gr o u ps ................................................................................................................... 2 6  
9. 7.  
C o m plia nce ................................................................................................................. 2 6  
9. 8.  
Baseli ne S u bject Data a n d Disease C haracteristics A nal yses .................................... 2 7  
9. 9.  
Efficac y A nal yses ....................................................................................................... 2 7  
9. 9. 1.  
Pri mar y Efficac y A nal ysis .......................................................................................... 2 7  
9. 9. 2.  
A nal ysis of t he Sec o n dar y Efficac y E n d p oi nts .......................................................... 2 8  
9. 9. 3.  
A nal ysis of t he e x pl orat or y Efficac y E n d p oi nts ......................................................... 2 8  
9. 9. 4.  
A nal ysis of Plas ma Bi o mar kers .................................................................................. 2 9  
9. 9. 5.  
S u m mar y of Reas o ns f or Efficac y N o n-e val ua bilit y/ E xcl usi o n fr o m Efficac y 
A nal yses ...................................................................................................................... 2 9  
9. 1 0.  
P har mac o ki netic A n al ysis .......................................................................................... 2 9  
9. 1 1.  
Safet y a n d T oler a bilit y A nal yses ................................................................................ 2 9  
9. 1 1. 1.  
Ge ner al Safet y A n al ysis Met h o ds .............................................................................. 2 9  
9. 1 1. 2.  
R o uti ne La b orat or y D ata ............................................................................................ 3 0  
9. 1 1. 3.  
Vital Si g ns a n d P h ysical E xa mi nati o n ........................................................................ 3 0  
9. 1 1. 4.  
Electr ocar di o gra m E v al uati o ns ................................................................................... 3 0  
9. 1 1. 5.  
C o nc o mita nt Me dicati o ns ........................................................................................... 3 0  
9. 1 1. 6.  
St u d y Ter mi nati o n Stat us ........................................................................................... 3 0  
1 0.  
R E F E R E N C E  ............................................................................................................. 3 1 
1 1.  
A P P E N DI X ................................................................................................................. 3 2 
1 1. 1.  
Ta ble of C o nte nts f or D ata Dis pla y S pecificati o ns .................................................... 3 2  
1 1. 1. 1.  
List of Ta bles .............................................................................................................. 3 2  
1 1. 1. 2.  
List of Fi g ures ............................................................................................................. 3 4  
1 1. 1. 3.  
Listi n gs ....................................................................................................................... 3 8  


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1 1. 2.  
Sa m ple Ta ble Te m plate .............................................................................................. 4 0  
1 1. 2. 1.  
Sa m ple Te m plate f or C o u nt Data ............................................................................... 4 1  
1 1. 2. 2.  
Sa m ple Te m plate f or C o nti n u o us Data ( Efficac y/ Safet y/ La b) ................................... 4 3  
 


EI P P har m a, I nc. 
 
 
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LI S T O F T A B L E S 
Ta ble 1: List of A b bre viati o ns ......................................................................................................... 7  
Ta ble 2: Sc he d ule of Assess me nts ................................................................................................. 1 2  
Ta ble 3: Cli nical La b orat or y A nal ytes ........................................................................................... 1 9  
 


EI P P har m a, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol # EI P 1 9- N F D - 4 0 1   
  
  
  
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
7 
 
 
  
 
1.  
LI S T O F A B B R E VI A TI O N S 
T a ble 1: List of A b bre vi ati o ns 
A b bre vi ati o n  
Defi niti o n 
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A S T  
As partate a mi n otra nsferase  
BI D  
bis i n die (t wice a da y)  
C A N T A B  
Ca m bri d ge Ne ur o ps yc h ol o gical Test A ut o mate d Batter y  
C R F  
Case re p ort f or m  
C R F  
Case re p ort f or m  
C- S S R S  
C ol u m bia -S uici de Se verit y Rati n g Scale  
E C G  
Electr ocar di o gra m  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G G T  
Ga m ma -Gl uta m yl Tra nsferase  
H D  
H u nti n gt o n’s Disease  
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 
L D H  
Lactate de h y dr o ge nase  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M O T  
M ot or Scree ni n g Tas k  


EI P P har m a, I nc. 
 
 
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M W M  
M orris Water Maze  
O T S  
O ne T o uc h St oc ki n gs of Ca m bri d ge  
P A L  
Paire d Ass ociate Lear ni n g  
P C S  
P ote ntiall y Cli nicall y Si g nifica nt  
P R M  
Patter n Rec o g niti o n Me m or y  
R TI  
Reacti o n Ti me  
S A E  
Seri o us A d verse E ve nt  
S D  
Sta n dar d De viati o n  
S R M  
S patial Rec o g niti o n Me m or y  
S S  
S patial S pa n  
T E A E  
Treat me nt E mer ge nt A d verse E ve nt  
T F C  
T otal F u ncti o nal Ca pacit y  
U H D R S  
U nifie d H u nti n gt o n's Disease Rati n g Scale  
 


EI P P har m a, I nc. 
 
 
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9 
 
 
  
 
2.  
I N T R O D U C TI O N 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he pla n ne d a nal yses a n d d ata 
dis pla ys t o be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R) f or Pr ot oc ol EI P 1 9- N F D - 4 0 1, 
Versi o n 2. 0, 2 0 Mar c h, 2 0 1 9. 
T his S A P is a m ore detaile d c o m pa ni o n t o t he Statistical Met h o ds secti o n of t he st u d y pr ot oc ol 
a n d pr o vi des a c o m pre he nsi ve descri pti o n of t he a nal ysis data sets, effi cac y e n d p oi nts, 
ass u m pti o ns, h o w missi n g data will be ha n dle d, as well as details o n statistical met h o ds will be 
use d t o a nal yze t h e saf et y a n d effi cac y d ata.  W h e n differe n ces e xist i n descri pti o ns or 
e x pla nati o ns pr o vi de d i n t he pr ot oc ol a n d t his a nal ysis pla n, t he S A P pre vails. T h e d oc u me nt 
ma y e v ol ve o ver ti me; f or e xa m ple, t o reflect t he re q uire me nts of pr ot o c ol a me n d me nts o r 
re g ulat or y r e q uests. T he fi nal S A P will be fi nalize d, a p pr o ve d b y t he S p o ns or, a n d place d o n file 
bef ore d ata bas e is l oc ke d.   De viati o ns fr o m t he fi nal a p pr o ve d pla n will be n ote d i n t he cli nical 
st u d y re p ort.  
 


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Statistical A nal ysis Pla n - Pr ot oc ol # EI P 1 9- N F D - 4 0 1   
  
  
  
 
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3.  
S T U D Y O B J E C TI V E S 
3. 1.  Pri m ar y O bjecti ve 
T o e val uate t he eff ects of a d mi nistrati o n of nefla m a pi m o d o n hi p p oca m pal f u ncti o n, as assesse d 
i n t he virt ual M orris Wat er Maze ( M W M). 
3. 2.  Sec o n d ar y O bjecti ve s 
•  T o e val uate t he eff ects of nefla ma pi m o d o n t he Ca m bri d ge Ne ur o ps y c h ol o gical Test 
A ut o mate d Batter y ( C A N T A B) paire d ass ociates lear ni n g tas k. 
•  T o e val uate eff ects of nefla ma pi m o d o n a lar ger batter y of para meters i n t he 
C A N T A B . 
•  T o e val uate t oler a bilit y a n d safet y of n efla ma pi m o d i n s u bjects wit h H u nti n gt o n 
Disease (H D ). 
 
3. 3.  E x pl or at or y Effic ac y  a n d S afet y  Objecti ves  
I n a d diti o n, e x pl orat or y a nal yses of t he f ull set of para meters i n t he C A N T A B will be c o n d ucte d 
a n d e x p os ure t o s afet y r elati o ns hi p will be i n vesti gate d if data all o w. 
 


EI P P har m a, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol # EI P 1 9- N F D - 4 0 1   
  
  
  
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
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4.  
S T U D Y D E SI G N  
T his is a P hase 2a, si n gle ce ntre, ra n d o mize d, d o u ble- bli n d, place b o- c o ntr olle d, 2- peri o d wit hi n-
s u bject cr oss o ver pr o of-of - pri nci ple st u d y of nefla ma pi m o d 4 0 m g or matc hi n g place b o 
a d mi nistere d t wice d ail y ( BI D) f or 1 0 wee ks i n s u bjects wit h Sta ge 1 H D. 
F oll o wi n g c o m pleti o n of i nf or me d c o nse nt pr o ce d ures, s u bjects will e nter t he Scree ni n g p h ase of 
t he st u d y. 
O ne scr ee ni n g visit is pla n ne d wit hi n 2 1 da ys bef ore baseli ne ( Da y 1), d uri n g w hic h ti me safet y 
scree ni n g meas ures a n d i nitial assess me nts, i ncl u di n g C A N T A B will be u n derta ke n a n d s u bject 
eli gi bilit y will be c o nfir me d. 
O nce eli gi bilit y is c o nfir me d a n d bef ore t he first d ose of st u d y dr u g, s u bjects will be ra n d o ml y 
assi g ne d o n a 1: 1 basis t o place b o or n efla ma pi m o d treat me nt d uri n g t he first treat me nt  peri o d  
(i.e., 8 s u bjects will recei ve nefla ma pi m o d a n d 8 will recei ve place b o d uri n g t he first treat me nt 
peri o d). I n vesti gat ors a n d s u bjects will be bli n de d t o t he treat me nt assi g n me nt. 
D osi n g will start o n Da y 1 f oll o wi n g c o m pleti o n of all baseli ne pr o ce d ures, w hic h will i ncl u de 
virt ual M orris Water Maze ( M W M) a n d C A N T A B tests. 
D uri n g t he treat me nt p eri o d, s u bjects will ret ur n t o t he cli nic e ver y 2 wee ks. 
At Wee ks 4 a n d 1 0 of t he first treat me nt peri o d, t h e virt ual M W M a n d C A N T A B tests will be 
re peat e d. 
All s u bjects will ret ur n f or a saf et y visit 2 wee ks after st o p pi n g dr u g i n t he first treat me nt peri o d. 
After at least 8 wee ks (a n d u p t o 1 2 wee ks) after c o m pleti o n of t he first treat me nt peri o d, 
s u bjects will ret ur n t o t he cli nic a n d after re p eati n g virt ual M W M a n d C A N T A B, will res u me 
bli n de d treat me nt; all s u bjects w h o recei ve d place b o ca ps ules d uri n g t he first treat me nt peri o d 
will recei ve n efla ma pi m o d, w hile t h ose w h o recei ve d nefla ma pi m o d will recei ve pl ace b o 
ca ps ules d uri n g t his sec o n d treat me nt peri o d. 
At t he e n d of Wee ks 4 a n d 1 0 of t he sec o n d treat m e nt peri o d, t he virt ual M W M a n d C A N T A B 
tests will be re peate d. 
A Fi nal St u d y Visit will be c o n d ucte d 2 wee ks aft er c o m pleti o n of t he sec o n d treat me nt peri o d. 
  
4. 1.  S a m ple Size J ustific ati o n  
N o f or mal sa m ple size calc ulati o n was perf or me d. A sa m ple size of 1 6 s u bj ects is c o nsi dere d 
a p pr o priate f or det er mi nati o n of t he preli mi nar y safet y a n d t olera bilit y of nefla ma pi m o d i n t his 
s u bject p o p ulati o n. 
 
4. 2.  St u d y d ur ati o n a n d visit sc he d ule  
T he st u d y d urati o n is 2 8 t o 3 2 wee ks ( 1 0 w ee ks of 1 st treat me nt peri o d + w as h o ut peri o d ( 8- 1 2 
wee k s) + 1 0 wee ks of 2n d treat me nt peri o d).  C o m plete descri pti o ns of t he assess me nts t o be 
perf or me d at eac h visit ar e liste d i n Ta ble 2. 


EI P P har m a, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -4 0 1   
 
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
1 2  
 
 
  
 
T a ble 2 : Sc he d ule of Assess me nts  
 
 
 
 
 
 
 
 
 
E v al u ati o n  
 
 
 
Scree ni n g a  
 
 
 
Tre at m e nt Peri o d 1  
W as h o ut 
( 8 t o 1 2 
wee ks)  
 
 
 
Tre at m e nt Peri o d 2  
 
E T  
Visit c 
Fi n al 
St u d y 
Visit d  
 
 
 
Wit hi n 
2 1 d a ys of  
D 1  
 
 
 
 
 
W 0
b  
 
 
 
W 2 
( ± 3) 
 
 
 
W 4 
( ± 3) 
 
 
 
W 6 
( ± 5) 
 
 
 
W 8 
( ± 5) 
 
 
 
W 1 0 
( ± 3) 
2 w ks  
( ± 3 d) of 
l ast d ose 
i n 
Peri o d 1  
 
 
 
 
 
W 0
b  
 
 
 
W 2 
( ± 3) 
 
 
 
W 4 
( ± 3) 
 
 
 
W 6 
( ± 5) 
 
 
 
W 8 
( ± 5) 
 
 
 
W 1 0 
( ± 3) 
Wit hi n 
3 d 
after 
l ast 
d ose  
 
 
 
2 w ks  
( ± 3 d) of 
l ast d ose 
I nf or me d C o nse nt 
X e 
P 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y 
re vie w 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y testi n g  
X f 
P 
X  
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
P h ysical 
e xa mi nati o n g  
P 
X  
 
 
 
 
 
X  
 
X  
 
 
 
 
X  
X  
X  
C -S S R S  
X  
 
 
 
 
 
X  
 
X  
 
 
 
 
X  
 
 
H os pital A n xiet y 
a n d De pressi o n 
Scale  
X  
 
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
 
 
U H D R S  
X  
 
 
 
 
 
X  
 
X  
 
 
 
 
X  
 
 
C A N T A B  
X  
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
 
M W M  
X  
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
 
Vital si g ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Pri or/c o nc o mita nt 
me dicati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse e ve nts 
rec or di n gh  
P 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
He mat ol o g y a n d 
c he mistr y i 
X  
X  
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
 
X  
 


EI P P har m a, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -4 0 1   
 
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
1 3  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
E v al u ati o n  
 
 
 
Scree ni n g a  
 
 
 
Tre at m e nt Peri o d 1  
W as h o ut 
( 8 t o 1 2 
wee ks)  
 
 
 
Tre at m e nt Peri o d 2  
 
E T  
Visit c 
Fi n al 
St u d y 
Visit d  
 
 
 
Wit hi n 
2 1 d a ys of  
D 1  
 
 
 
 
 
W 0
b  
 
 
 
W 2 
( ± 3) 
 
 
 
W 4 
( ± 3) 
 
 
 
W 6 
( ± 5) 
 
 
 
W 8 
( ± 5) 
 
 
 
W 1 0 
( ± 3) 
2 w ks  
( ± 3 d) of 
l ast d ose 
i n 
Peri o d 1  
 
 
 
 
 
W 0
b  
 
 
 
W 2 
( ± 3) 
 
 
 
W 4 
( ± 3) 
 
 
 
W 6 
( ± 5) 
 
 
 
W 8 
( ± 5) 
 
 
 
W 1 0 
( ± 3) 
Wit hi n 
3 d 
after 
l ast 
d ose  
 
 
 
2 w ks  
( ± 3 d) of 
l ast d ose 
C oa g ulati o n st u dies i 
X  
 
 
X  
 
 
 
X  
 
 
X  
 
 
 
 
X  
1 2 -lea d 
electr ocar di o gra m j 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dis pe nse st u d y 
dr u g k  
 
X  
X  
X  
X  
X  
 
 
X  
X  
X  
X  
X  
 
 
 
Fi nal st u d y dr u g 
rec o nciliati o n 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
X  
 
C A N T A B = Ca m bri d ge Ne ur o ps yc h ol o gical Test A ut o mate d Batter y; C -S S R S: C ol u m bia -S uici d e Rati n g Scale; D = Da y; E T = E n d -of -Treat me nt; M W M = M orris Water Maze; 
U H D R S = U nifie d H u nti n gt o n's Disease Rati n g Scale; W = Wee k.  
a. 
All scree ni n g assess me nts s h o ul d be c o n d ucte d wit hi n 2 1 d a ys of Da y  1.  
b.  
At Wee k 0 of eac h treat me nt peri o d, all pr oce d ures s h o ul d b e c o n d u cte d pri or t o first d ose of st u d y  dr u g.  
c. 
S u bjects w h o pre mat urel y disc o nti n ue st u d y dr u g f or a n y reas o n will b e as k e d t o ret ur n t o t h e cli nical site f or a n Earl y Ter mi nati o n visit wit hi n 3 d a ys f oll o wi n g t he last 
st u d y dr u g d ose; if it is deter mi ne d t hat t he s u bject will disc o nti n u e st u d y dr u g w hile at t h e st u d y ce nter f or a sc h e d ule d v isit, t h e n t h e Earl y Ter mi nati o n visit s h o ul d be 
c o n d ucte d at t hat  ti me. 
d.  
T he F oll o w -u p Visit s h o ul d be c o n d ucte d wit hi n 2 wee ks ( ± 3 d a ys) of t h e last d ose of st u d y dr u g f or s u bjects w h o c o m plete t he st u d y or d isc o nti n ue earl y. 
e. 
I nf or me d c o nse nt pr oce d ures, i ncl u di n g si g ni n g of i nf or me d c o nse nt, m ust b e c o m plete d b ef ore a n y st ud y -s pecific pr oce d ures are p erf or me d.  
f. 
Fe male s u bjects of c hil d -beari n g p ote ntial or w h o h a v e reac h e d me n o p a use i n t h e pre vi o us y ear m ust h a v e a ser u m or uri ne pre g na nc y test perf or me d d uri n g Scree ni n g, 
W ee k 0, e ver y 4 wee ks d uri n g t he 1 st a n d 2 n d treat me nt p eri o ds, a n d at t h e F oll o w -u p Visit; s u bjects wit h p ositi v e res ults are n ot eli gi ble f or st u d y  partici pati o n.  
g.  
Refer t o Secti o n 6. 2. 7 of t he st u d y pr ot oc ol f or details re g ar di n g p h ysical e x a mi n ati o n. 
h.  
Defi niti o ns  a n d  pr oce d ures  f or d oc u me nti n g  a n d  re p orti n g A Es  seri o us a d v erse e v e nts ( S A Es) are pr o vi d e d  i n Secti o n  7 of t he st u d y pr ot oc ol . 
i. 
Details  of  cli nical la b orat or y sa m pli n g f or c he mistr y,  h e mat ol o g y,  a n d  c o a g ulati o n st u dies are disc us se d i n Secti o n  6. 2. 9 of t he st u d y pr ot oc ol . 
j. 
Details of 1 2 -lea d E C G assess me nt are disc usse d i n Secti o n 6. 2. 8 of t h e st u d y pr ot o c ol . 
k.  
St u d y dr u g details i ncl u di n g pac ka gi n g, st ora ge, acc o u nta bilit y, a n d d osi n g are prese nte d i n Secti o n  5 of t h e st u d y pr ot oc ol . 
 


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 1 4  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
5.  
C LI NI C A L A S S E S S M E N T S  
5. 1.  B aseli ne a n d Dise ase C h ar acteristics  
Details re gar di n g H D hist or y will be c ollecte d d uri n g Scree ni n g, as s pecifie d i n t he C R F. 
 
5. 2.  Effic ac y Assess me nts  
5. 2. 1.  
M orris W at er M a ze Test 
T he M W M test is use d t o assess hi p p oca m pal- d e p e n de nt s patial lear ni n g a n d me m or y ( M orris, 
1 9 8 4 ). A virt ual-r ealit y versi o n of M W M test is t o be a d mi nistere d at t he ti me p oi nts s pecifie d i n 
Ta ble 2 . T his tas k is a h u ma n a nal o g ue of t h e classic M W M tas k c o m m o nl y use d i n r o de nt 
st u dies. Patie nts were t ol d t o na vi gate t hr o u g h a virt ual 3- di me nsi o nal p o ol prese nte d o n t he 
scree n usi n g a j o ystic k. T he g oal of t he test is t o fi n d a n d re me m ber t he l ocati o n of a hi d de n 
platf or m, usi n g vis ual c ues place d o n t he walls. Patie nts ha ve a first- pers o n vie w p oi nt wit h a 
fiel d of vie w c o m p ara ble t o t he h u ma n e ye. 
5. 2. 2.  
C A N T A B  
T he C A N T A B batter y w as de vel o pe d f or t he ass ess me nt of c o g niti ve deficits i n h u ma ns wit h 
ne ur o de ge n er ati ve diseas es or brai n da m a ge. It c o nsists of a series of i nterrelate d c o m p uteri ze d 
tests of me m or y, atte nti o n, a n d e xec uti ve f u ncti o n, a d mi nistere d via a t o uc h-se nsiti ve scree n 
(Fr a y  a n d R o b bi ns, 1 9 9 6). S pecificall y, C A N T A B tests i ncl u de: 
•  
M ot or Scree ni n g Tas k: 2 mi n utes 
•  
Reacti o n Ti me: 3 mi n utes 
•  
Paire d Ass ociates L ear ni n g: 8 mi n utes 
•  
O ne T o uc h St oc ki n gs of Ca m bri d ge: 1 0 mi n utes 
•  
S patial S pa n: 5 mi n utes 
•  
S patial Rec o g niti o n Me m or y: 5 mi n utes 
•  
Patter n Rec o g niti o n Me m or y: 4 mi n utes 
T he C A N T A B is t o be a d mi nistere d at t he ti me p oi nts s pecifie d i n Ta ble 2. 
 
C A N T A B M ot or Scree ni n g T as k ( M O T) : 
T he M O T ser v es as a g e neral i ntr o d ucti o n t o t he C A N T A B batter y a n d pr o vi des a ge neral 
assess me nt of w het h er se ns ori m ot or deficits or lac k of c o m pre h e nsi o n, will li mit t he c ollecti o n 
of vali d data fr o m t he p artici pa nt. C ol o ure d cr osses are prese nte d i n differe nt l ocati o ns o n t he 
scree n, o n e at a ti me. T h e partici pa nt m ust select t he cr oss o n t he scree n as q uic kl y a n d 
acc ur atel y as p ossi ble. 
C A N T A B Re acti o n Ti m e ( R TI): 


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EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
R TI pr o vi d es a n ass ess me nt of m ot or a n d me ntal res p o nse s pee ds, as well as meas ures of 
m o ve me nt ti me, reacti o n ti me, res p o nse acc urac y a n d i m p ulsi vit y. T he partici pa nt m ust select 
a n d h ol d a b utt o n at t he b ott o m of t he scree n. Circl es are prese nt e d a b o ve ( o ne f or t he si m ple 
m o de, a n d fi ve f or t he fi v e-c h oice m o de.) I n eac h case, a y ell o w d ot will a p pear i n o ne of t he 
circles, a n d t h e partici pa nt m ust react as s o o n as p ossi ble, releasi n g t he b utt o n at t he b ott o m of 
t he scree n, a n d selecti n g t he circle i n w hic h t h e d ot a p peare d. 
C A N T A B P aire d Ass oci ate Le ar ni n g ( P A L): 
D uri n g t he P A L, partici p a nts are r e q uire d t o re me m ber t he l ocati o ns of a n u m ber of differe nt 
o bjects w hic h ar e hi d de n i nsi de b o xes o n t he c o m p uter scree n. T his tas k re q uires t he partici pa nt 
t o lear n t o pair t w o ite ms i n me m or y - i n t his case t he t y pe of o bject a n d t h e l ocati o n of t he 
o bject. W he n o n e of t he paire d f eat ures is re veale d (i n t his case t he o bject), t he partici pa nt is 
as ke d t o re me m b er its ass ociate (t he l ocati o n it is hi d de n i n). T his t y pe of lear ni n g is esse ntial i n 
e ver y da y life, f or e xa m pl e w he n lear ni n g ne w w or ds. W he n y o u lear n a ne w w or d, n ot o nl y d o 
y o u lear n t he w or d itself, b ut y o u ha ve t o pair t his wit h t he mea ni n g it re prese nts 
C A N T A B S p ati al S p a n ( S S): 
S S tests s patial me m or y s pa n b y meas uri n g a bilit y t o me m orize t he or d er i n w hic h a n i ncreasi n g 
n u m ber of w hite b o xes c ha n ge c ol or. T h e s patial s pa n tas k relies o n vis u os patial w or ki n g 
me m or y; t he c o m p o ne nt of w or ki n g me m or y t hat all o ws y o u t o te m p oraril y h ol d a n d ma ni p ulate 
i nf or mati o n a b o ut places. Ma n y e ver y d a y acti vities i n v ol ve vis u os patial w or ki n g me m or y, 
i ncl u di n g fi n di n g y o ur wa y ar o u n d y o ur e n vir o n m e nt, j u d gi n g t he p ositi o n of ot her m ot orists 
w hile y o u are dri vi n g a n d searc hi n g f or y o ur k e ys. Acc or di n g t o o ne v er y i nfl ue ntial c o g niti ve 
m o del of w or ki n g me m or y ( Ba d derl y & Hitc h, 1 9 7 4) vis u os patial w or ki n g me m or y de pe n ds o n a 
s pecialize d s u b- c o m p o ne nt of t he w or ki n g me m or y s yste m. T his is referre d t o as t he 
“ vis u os patial s ketc h pa d” a n d is t h o u g ht t o ha ve a vis ual “cac h e”, res p o nsi ble f or st ori n g vis ual 
f or m a n d c ol or i nf or mati o n, a n d a n “i n ner scri be” w hic h deals wit h s patial a n d m o ve me nt 
i nf or mati o n. T his tas k places si g nifica nt d e ma n ds o n t he i n ner scri be. 
C A N T A B O ne T o uc h St oc ki n gs of C a m bri d ge ( O T S): 
E xec uti ve f u n cti o ns are a set of c o g niti ve s kills t hat hel p us t o re g ulate t he ot her me n tal 
pr ocesses t hat are n ecess ar y t o c o m plete e v er y d a y acti vities. T he y all o w us t o pr o d uce c o m ple x 
g oal directe d t h o u g hts a n d be ha vi ors s uc h as pla n ni n g f ut ure e ve nts, carr yi n g o ut tas ks wit h 
m ulti ple sta ges a n d o verc o mi n g ha bit ual res p o nses. E xec uti ve f u n cti o ns pr o vi de us wit h t he 
a bilit y t o d y na micall y a dj ust a n d re g ulate be h a vi or o n t he basis of i nter nal re pres e ntati o ns a n d 
e xter nal f ee d b ac k.  T he O T S meas ures t he e xec uti ve f u ncti o ns of s patial pl a n ni n g a n d w or ki n g 
me m or y a bilit y. T he patie nt is s h o w n t w o dis pla ys c o ntai ni n g t hree c ol ore d balls, prese nte d s o 
t he y ca n be p ercei ve d as stac ks of c ol ore d balls i n st oc ki n gs. I n eac h tri al, t he patie nt m ust 
i ma gi ne m o vi n g t he balls i n t he l o wer dis pla y t o c o p y t he patter n s h o w n i n t he u p per, a n d 
calc ulate h o w ma n y ‘ m o ves’ t his w o ul d ta ke. Pla n ni n g a bilit y is i n de xe d b y t he n u m ber of 
pr o ble ms s ol ve d at t he first atte m pt at eac h le v el of diffic ult y. T he O T S will be use d i n t his st u d y 
t o deter mi ne w het her perf or ma nce o n t he s ocialit y e x peri me nts has a n y relati o ns hi p t o deficits i n 
e xec uti ve f u n cti o n i n H D. 
C A N T A B S p ati al Rec o g niti o n Me m or y ( S R M) 


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T he S R M is a test of s patial rec o g niti o n me m or y a n d is li n ke d t o fr o ntal l o be f u ncti o n ( O w e n et 
al, 1 9 9 5). I n t he e n c o di n g p hase, partici p a nts are s h o w n a series of w hite s q uares w hic h are 
prese nte d at differ e nt l ocati o ns o n a blac k scree n a n d i nstr ucte d t o re me m b er w here eac h s q uare 
a p pears. I n t he r ec o g niti o n p hase partici p a nts are s h o w n t w o s q uares, i n differe nt l ocati o ns, a n d 
as k t o i de ntif y t he o ne t h at is i n t he sa me place as o ne t he y ha ve b ee n s h o w n pre vi o usl y. S patial 
rec o g niti o n me m or y is i n de x b y t he perce nta g e of place me nts c orrectl y disti n g uis he d fr o m 
distract or place me nts. 
C A N T A B P atter n Rec o g niti o n Me m or y ( P R M) 
T he P R M is a test of vis ual rec o g niti o n me m or y a n d is li n ke d t o hi p p oca m pal f u ncti o n (O w e n et 
al, 1 9 9 5). I n t he e n c o di n g p hase, partici p a nts are s h o w n wit h a series of a bstract li ne dra wi n gs 
prese nte d o n e at a ti me i n t he ce ntre of a bla n k s cree n. T h e y are i nstr ucte d t o re me m ber t he 
patter ns. D uri n g t he r ec o g niti o n p hase, t w o a bstract li ne dra wi n gs are prese nte d o n t he scree n, 
si de b y si de a n d partici pa nts are as ke d t o i de ntif y t he o ne t he y ha v e pre vi o usl y bee n s h o w n. 
Vis ual rec o g niti o n me m or y is i n de xe d b y t he perce nta ge of p atter ns c orrectl y disti n g uis he d fr o m 
n o vel distract ors. 
 
5. 3.  Ot her Cli nic al  Assess me nts  
5. 3. 1.  
C ol u m bi a- S uici de Se verit y R ati n g Sc ale 
T T he C- S S R S is a cli nicia n-a d mi nistere d i nstr u m e nt t hat assesses s uici dal i deati o n a n d be ha vi or 
(P os ner et al, 2 0 1 1 ).  T h e “ Baseli ne” v ersi o n of t h e i nstr u me nt will be a d mi nistere d t o s u bjects 
d uri n g Scree ni n g a n d b ef ore be gi n ni n g t he sec o n d treat me nt peri o d, a n d t he “ Si nce Last Visit” 
versi o n will be use d at all ot her ti me p oi nts s pecifie d i n Ta ble 2. 
5. 3. 2.  
H os pit al A n xiet y a n d De pressi o n Sc ale 
T he H os pital A n xiet y a n d De pressi o n Scal e is a 1 4-ite m self-assess me nt scale desi g ne d t o 
deter mi ne t he de gree of a n xiet y a n d de pressi o n a p atie nt is e x perie nci n g ( Zi g m o n d, S nait h, 
1 9 8 3 ). Eac h ite m o n t he q uesti o n naire is sc ore d fr o m 0- 3; t h us, t otal sc ores ra n ge fr o m 0 a n d 2 1 
f or eit her a n xiet y or de pr essi o n. T he H os pital A n xiet y a n d De pressi o n Scale is t o be c o m plete d 
at t he ti me p oi nts s pecifie d i n Ta ble 2. 
5. 3. 3.  
U nifie d H u nti n gt o n's Dise ase R ati n g Sc ale 
T he  U H D R S  was  de vel o pe d  as  a  cli nical  rati n g  scale  t o  assess  4  d o mai ns  of  cli nical 
perf or ma n ce  a n d  ca pacit y  i n  H D:  m ot or  f u ncti o n,  c o g niti ve  f u ncti o n,  be ha vi oral 
a b n or malities, a n d f u ncti o nal ca pacit y ( H u nti n gt o n St u d y Gr o u p, 1 9 9 6 ). 
•  
T he m ot or secti o n of t he U H D R S assesses m ot or feat ures of H D wit h sta n dar dize d rati n gs of 
oc ul o m ot or f u ncti o n, d ysart hria, c h orea, d yst o nia, gait, a n d p ost ural sta bilit y. A 
de m o nstrati o n of t he tec h ni q ues of t he m ot or e xa m a n d e xa m ples of eac h gra de of 
a b n or malit y are pr o vi de d o n t he acc o m pa n yi n g vi de ota pe. T he t otal m ot or i m pair me nt sc ore 
is t he s u m of all t he i n di vi d ual m ot or rati n gs, wit h hi g her sc ores i n dicati n g m ore se vere m ot or 
i m pair me nt t ha n l o wer sc ores. 


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•  
C o g niti ve o per ati o ns are assesse d b y a p h o netic ver bal fl ue nc y test, S y m b ol Di git 
M o dalities Test, a n d t he Str o o p I nterfere nce Test. T he Str o o p Test res ults are re p orte d as t he 
ra w n u m ber of c orrect a ns wers gi ve n i n a 4 5-sec o n d peri o d. Res ults f or t he ot her tests are 
re p orte d as t he ra w n u m ber of c orrect res p o nses. Hi g her sc ores i n dicate better c o g niti ve 
perf or ma nce.  
•  
T he be h a vi or al assess me nt meas ures t he fre q ue nc y a n d se verit y of s y m pt o ms relate d t o 
affect, t h o u g ht c o nte nt a n d c o pi n g st yles. T he t otal be ha vi or sc ore is t he s u m of all 
res p o nses; h o we ver, t his sc ore ma y ha ve less usef ul ness t ha n t he i n di vi d ual s u bscale sc ores 
f or m o o d, be ha vi or, ps yc h osis, a n d o bsessi ve ness w hic h are create d b y s u m mi n g t he 
res p o nses t o t he c orres p o n di n g q uesti o ns. T he e val uat or is als o re q ueste d t o pr o vi de a 
cli nical i m pressi o n as t o w het her t he patie nt, at t he ti me of t he e val uati o n, has cli ni cal 
e vi de nce of c o nf usi o n, de me ntia, or de pressi o n a n d w het her t he patie nt re q uires 
a nti de pressa nt t hera p y, acc or di n g t o preset defi niti o ns i n t he e xa mi nati o n g ui deli nes. Hi g her 
sc ores o n t he be ha vi or assess me nts i n dicate m ore se vere dist ur ba nce t ha n l o wer sc ores. 
•  
T he f u ncti o n al assess me nts i ncl u de t he H D F C S, t he I n de pe n de nce scale, a n d a c hec klist 
of c o m m o n dail y tas ks. F or t he latter ite ms, t he i n vesti gat or i n dicates if t he patie nt c o ul d 
perf or m t he tas k. T he c hec klist is s u m me d b y gi vi n g a sc ore of 1 t o all “ yes” re plies. T he 
H D F C S  is re p orte d as t he t otal f u ncti o nal ca pacit y ( T F C) sc ore. T h e i n de pe n de nce 
scale is rate d fr o m 0 t o 1 0 0, wit h hi g her sc ores o n t he f u ncti o n scales i n dicati n g 
better f u ncti o ni n g t ha n l o wer sc ores. 
 
T he U H D R S is t o be a d mi nistere d at t he ti me p oi nts s pecifie d i n Ta ble 2. N ote t hat at Wee k 4 i n 
eac h tr eat me nt peri o d, o nl y t he m ot or m o d ule nee d be a d mi nistere d. 
 
 
5. 4.   P h ysic al E x a mi n ati o n a n d Vit al Si g ns  
P h ysical e xa mi nati o n will i ncl u de a re vie w of all b o d y s yste ms a n d meas ure me nt of wei g ht, per 
eac h I n v esti gat ors sta n dar d practice. P h ysical e xa mi nati o n fi n di n gs will be d oc u me nte d i n t he 
s u bject’s s o urce d oc u me nts. 
Vital si g ns i ncl u de meas ure me nt of bl o o d press ure, p ulse, res pirat or y rat e, a n d b o d y te m perat ure. 
A n y p h ysical e xa mi nati o n fi n di n g or vital si g n meas ure me nt t hat re pres e nts a w orse ni n g fr o m 
Baseli ne c o n diti o n a n d is c o nsi dere d b y t he I n vesti gat or t o be cli nicall y si g nifica nt will be 
rec or d e d as a n A E.   T he ti mi n g of assess me nts ca n be f o u n d i n t he sc he d ul e of assess me nts i n 
Ta ble 2. 
 


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5. 5.  1 2 -Le a d Electr oc ar di o gr a m  
A 1 2-lea d E C G will be p erf or me d usi n g v ali date d mac hi ner y a v aila ble l ocall y t o eac h cli nical 
site. Eac h re p ort will be r e vie we d b y t he i n v esti gat or f or q ualifie d s u b-i n vesti gat or a n d assesse d 
as n or mal, a b n or mal – n ot cli nicall y si g nifica nt, or a b n or mal – cli nicall y si g nifica nt. A b n or mal, 
cli nicall y si g nifica nt fi n di n gs t hat re prese nt a w ors e ni n g fr o m Baseli ne will be rec or de d as a n 
a d verse e ve nt. 
 
5. 6.  Cli nic al L a b or at or y Assess me nt  
T w o bl o o d sa m ples will be c ollecte d at t he ti me p oi nts s pecifie d i n Ta ble 2 f or assess me nt of 
r o uti ne c he mistr y a n d he mat ol o g y a nal ytes. O ne a d diti o nal bl o o d sa m ple will be c ollecte d f or 
c oa g ulati o n st u dies at t he ti me p oi nts s pecifie d i n Ta ble 2. Cli nical la b orat or y fi n di n gs t hat 
re pres e nt a w ors e ni n g fr o m Baseli ne val ue a n d are c o nsi dere d b y t he i n v esti gat or t o be cli nicall y 
si g nifica nt will be rec or d e d as a n a d v erse e ve nt. T a ble 3 lists t he a nal ytes fr o m r o uti ne 
c he mistr y, he mat ol o g y a n d c oa g ulati o n st u dies. Cli nical la b orat or y fi n di n gs t hat re pres e nt a 
w orse ni n g fr o m Baseli ne val ue a n d are c o nsi d ere d b y t he i n vesti gat or t o be cli nicall y si g nifica nt 
will  be rec or d e d as a n a d verse e v e nt.  
 
 


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T a ble 3: Cli nic al L a b or at or y A n al ytes 
Ser u m C he mistr y  
He m at ol o g y 
Al b u mi n 
Differe ntial (a bs ol ute a n d perce nt): 
Al kali ne P h os p hatase 
Bas o p hils 
Ala ni ne A mi n otra nsferas e ( A L T) 
E osi n o p hils 
As partate A mi n otra nsfer ase ( A S T) 
L y m p h oc ytes 
Bilir u bi n (t otal a n d direct) 
M o n oc ytes 
Gl uc ose 
Ne utr o p hils 
Bl o o d Urea Nitr o ge n 
Er yt hr oc ytes: 
Calci u m 
Mea n c or p us c ular h e m o gl o bi n ( M C H) 
Bicar b o nate 
Mea n c or p us c ular h e m o gl o bi n 
c o nce ntrati o n ( M C H C)  
C hl ori de 
Mea n c or p us c ular v ol u m e ( M C V) 
T otal c h olester ol 
He m o gl o bi n 
Tri gl yceri des 
Le u k oc ytes 
Creati ni ne 
Platelets  
Ga m ma - Gl uta m yl Tra nsf erase ( G G T) 
C o a g ul ati o n St u dies  
  
Lactate d e h y dr o ge n ase ( L D H) 
P h os p hate 
 Pr ot hr o m bi n ti me  
P otassi u m 
 Partial t hr o m b o plasti n ti me 
S o di u m 
 I N R 
T otal pr otei n 
  
Uric aci d 
  
 
 


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6.  
D E FI NI TI O N S , C O N V E N TI O N S  A N D D E RI V E D V A RI A B L E S  
6. 1.  
Defi niti o ns a n d c o n ve nti o ns  
 
A ge 
T he s u bject a g e ( years) is calc ulate d b ase d o n i nf or me d c o nse nt dat e a n d birt h date. 
 
B aseli ne 
Baseli ne is defi ne d as t he meas ure me nt pri or t o first d ose of st u d y me dicati o n at st u d y Da y 1 of 
eac h p eri o d. If f or a n y p ara meter t h e st u d y Da y 1 pre- d ose v al ue is n ot d o ne or missi n g, t he n t he 
val ue o btai ne d at a Scree ni n g visit is use d as Baseli ne.   
 
C o nc o mit a nt m e dic ati o n 
C o nc o mita nt me dicati o ns are defi ne d as a n y me di cati o ns o n g oi n g at t he start of treat me nt or wit h 
a start date a n d ti me o n or after t h e date of first st u d y me dicati o n d ose at st u d y Da y 1 t hr o u g h t he 
e n d of st u d y.    A si n gle me dicati o n ma y be pri or, c o nc o mita nt a n d p ost-treat me nt.  ( See als o 
pri or me dicati o n a n d p ost-treat me nt me dicati o n i n t his secti o n) 
 
I nf or m e d c o nse nt d ate 
I nf or me d c o ns e nt date is deter mi ne d b y t he c orres p o n di n g fiel d i n t he data base.  
 
Missi n g Me dic ati o n D ates 
Me dicati o ns wit h missi n g or partial start dat es will be classifie d t o a n y me dicati o n assi g n me nt 
t hat t he a vaila ble i nf or m ati o n all o ws.  S h o ul d a st o p date e xist, t he st o p dat e will be ta ke n i nt o 
acc o u nt.  F or e x a m ple, if a me dicati o n has a missi n g start date, b ut t he st o p date is pri or t o first 
d ose date, t he me dicati o n will o nl y be classifie d as pri or.  H o we v er, if a m e dicati o n has a 
missi n g start date a n d t he st o p date occ urs o n t he l ast da y of treat me nt, t he me dicati o n will be 
classifie d as pri or a n d c o nc o mita nt.  Si milarl y, partial starts will use t he a v aila ble data t o ai d i n 
t he classificati o n.   
If t he st o p date is missi n g or o n g oi n g, t he me dicati o n will be classifie d bas e d o n t he start date 
a n d t he n t o all s u bse q ue nt assi g n me nts.  If t here is partial st o p date i nf or mati o n, t he a vaila ble 
data will be use d t o ai d i n t he classificati o n.  
 
P ost-tre at m e nt m e dic ati o n 
A p ost-treat me nt me dicati o n is defi ne d as a n y me dicati o n o n g oi n g or wit h a start date a n d ti me 
after t he l ast da y of treat me nt.   A si n gle me dicati o n ma y be pri or, c o n c o mita nt a n d p ost-
treat me nt.  ( See als o pri or me dicati o n a n d c o n c o mita nt me dicati o n i n t his secti o n) 


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Pri or m e dic ati o n 
Pri or me dicati o ns are d efi ne d as a n y me dicati o ns ta ke n pri or t o first d ose of st u d y me dicati o n at 
t he be gi n ni n g of t he st u d y.    A si n gle me dicati o n ma y be pri or, c o n c o mita nt, a n d p ost-treat me nt.   
 
6. 2.  
Deri ve d V ari a bles  
6. 2. 1.  
C h a n ge fr o m B aseli ne at e ac h tre at me nt peri o d 
C ha n ge fr o m bas eli ne at eac h tr eat me nt peri o d is defi ne d as t he p ost- b aseli ne val ue mi n us t he 
baseli ne val ue at eac h peri o d. 
6. 2. 2.  
Tre at m e nt Differe nce of C h a n ge fr o m B aseli ne wit hi n S u bject Bet w ee n Peri o ds 
T he treat me nt diff er e nce f or a s u bject is c h a n ge fr o m baseli ne at t he nefla ma pi m o d treat me nt 
peri o d mi n us t he c ha n ge fr o m baseli ne at t he pl ace b o treat me nt peri o d wit hi n t he sa me s u bject. 


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7.  
A N A L Y SI S P O P U L A TI O N S  
7. 1.  
S afet y P o p ul ati o n  
T he safet y p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve at least 1 d ose of st u d y 
dr u g nefla ma pi m o d . 
7. 2.  
E v al u a ble  Effic ac y P o p ul ati o n ( E E P) P o p ul ati o n  
T he E val ua ble Efficac y P o p ulati o n ( E E P) p o p ulati o n will be all s u bjects w h o ha ve b ot h a 
baseli ne a n d at least o ne o n-st u d y assess me nt of t he effi cac y p ara m eter ( C A N T A B batter y a n d/ or 
M W M) bei n g e v al uate d.  
7. 3.  
C o m pleter  P o p ul ati o n  ( C P) 
T he C o m pleter P o p ulati o n will be s u bjects w h o ha ve c o m plete d b ot h peri o ds of o n-st u d y 
assess me nt of t he efficac y para meter ( C A N T A B batter y a n d/ or M W M) bei n g e val uate d. 
 
 


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8.  
D A T A M A N G E M E N T , R E VI E W  A N D P R E E S E N T A TI O N  
8. 1.  D at a M a n a ge me nt  a n d Q u alit y Ass ur a nce  C o nsi der ati o ns  
T his st u d y will e m pl o y case re p ort f or ms ( C R Fs ). T he site will be trai ne d o n s pecific f or ms a n d 
pr oce d ur es f or s o urce d o c u me ntati o n a n d mai nte n a nce of a n a u dit trail of t he data t hat is e ntere d 
o n t he C R F pri or t o st u d y i nitiati o n. 
St u d y pers o n nel at eac h site will e nter data fr o m s o urce d oc u m e nts c orres p o n di n g t o a s u bject’s 
visit o nt o t he pr ot oc ol-s pecific C R F  w h e n t he i nf or mati o n c orres p o n di n g t o t hat visit is a vaila ble. 
T he I n vesti gat ors will pr e pare a n d mai ntai n a d e q uate a n d acc urate s o urce d oc u me nts desi g ne d t o 
rec or d all o bser vati o ns a n d ot her perti ne nt dat a f or eac h s u bj ect treate d wit h t he st u d y dr u g. 
T he I n vesti gat or is r es p o nsi ble f or all i nf or mati o n c ollecte d o n s u bjects e nr olle d i n t his st u d y. All 
data c ollecte d d uri n g t he c o urse of t his st u d y m ust be re vie w e d a n d v erifie d f or c o m plete n ess 
a n d acc urac y b y t he I n v esti gat or. 
S u bjects a n d site pers o n n el ass ociate d wit h st u d y c o n d uct will be bli n de d t o treat me nt 
assi g n me nt. Treat me nt c o des will be pr o vi de d i n seale d e n v el o pes t o t he site a n d will be st ore d 
b y t he p har macist or d esi g nee. 
D uri n g t he c o n d uct of t h e st u d y, t he bli n d s h o ul d be br o ke n o n a n i n di vi d ual s u bject basis i n t he 
e ve nt of a n e mer g e nc y w here it is necessar y f or t he I n vesti gat or t o k n o w w hic h treat me nt t he 
s u bject is recei vi n g bef or e t he s u bject ca n be treat e d. T he c o d e ma y als o be br o ke n if s o me o ne 
n ot i n t he st u d y uses st u d y dr u g (e. g., if a c hil d i n t he partici pa nt’s h o us e h ol d ta kes st u d y dr u g, 
t he bli n d ma y be br o ke n t o deter mi ne treat me nt f or t he c hil d.) 
Q ueries will be iss ue d f or a n y i nc o nsiste ncies, o missi o ns, a n d discre pa ncies a n d will be res ol ve d 
b y t he a p pr o priat e parties. 
Data base l o c k will occ ur o nce q ualit y ass ura n ce pr oce d ures h a ve b ee n c o m plete d. 
All A Es will be c o de d usi n g t he latest versi o n of t he Me dical Dicti o nar y f or Re g ulate d Acti vities 
( Me d D R A). C o nc o mita nt me dicati o ns will be c o de d usi n g t he latest versi o n of t he W orl d H ealt h 
Or ga nizati o n Dr u g Dicti o nar y. 
All pr oce d ures f or t he h a n dli n g a n d a nal ysis of data will be c o n d ucte d usi n g g o o d c o m p uti n g 
practices m eeti n g U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A), E ur o pea n Me dici nes 
A ge nc y, a n d I C H g ui deli nes f or t he ha n dli n g a n d a nal ysis of data f or cli nical st u dies. Data 
ma na ge me nt details will be o utli ne d i n a se parate data ma na g e me nt pla n. 
  
8. 2.  D at a Prese nt ati o n  
T he data will be pr ese nte d i n sta n dar d i n di vi d ual s u bject data listi n gs. T he listi n gs will i ncl u de 
s u bject i de ntificati o n n u m ber, de m o gra p hi cs, a n d treat me nt. Selecte d listi n gs will be i ncl u de d i n 
t he Cli nical St u d y Re p ort. I n d ata s u m maries, d escri pti ve statistics ( n, arit h metic mea n, sta n dar d 
de viati o n [ S D], me dia n, l o wer a n d u p p er q uartiles, mi ni m u m a n d ma xi m u m val ues) will be 
prese nte d f or c o nti n u o us varia bles. C o u nts a n d perce nta ges will be prese nte d f or cat e g orical 
varia bles.  


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8. 3.  I nteri m D at a Re vie w 
N o i nteri m a nal ysis is pla n ne d. 


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9.  
S T A TI S T SI C A L M E T H O D O L O G Y 
All statistical a nal yses will be perf or me d usi n g S- P L U S ( Versi o n 8. 2) or S A S ( Versi o n 9. 3 or 
hi g her).   T he v ersi o n e m pl o ye d at t he st u d y start will be mai ntai ne d t hr o u g h o ut t he pr oject. 
9. 1.  Ge ner al St atistic al Met h o d ol o g y  
Data will be ta b ulate d b y treat me nt gr o u p b y st u d y peri o d, wit h data listi n gs pr o vi de d f or all dat a 
ca pt ure d i n t he C R F i ncl u di n g la b orat or y data.  O n-treat me nt data will be assesse d descri pti vel y 
as b ot h o bser ve d v al ues a n d as c ha n ges fr o m bas eli ne.  W he n ta b ulat e d, dat a will be prese nt e d 
usi n g descri pti ve statistics.  M ost c o nti n u o us data will be s u m marize d wit h t he f oll o wi n g 
descri pti ve statistics u nless ot her wise n ote d: n u m ber of o bser vati o ns, mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m; i nter q uartile ra n ges will be pr o vi de d as a p pr o priate.  
Cate g orical data will be s u m marize d wit h fre q ue n cies a n d perce nt a ges. 
Miss i n g data will n ot be i m p ute d u nless ot her wise d oc u me nte d i n t his S A P. U nless state d 
ot her wise, statistical tests c o n d ucte d will be t w o-si de d at a le v el of 0. 0 5. N o a dj ust me nt f or 
m ulti plicit y will be ma de. 
Paire d t-test will be use d t o test t he differe n ce b et wee n treat me nts if t he tar get metric is n or mall y 
distri b ute d (s y m metrical distri b ut e d at t he mi ni mal), ot her wise, t he n o n para metric a p pr o ac h -
Wilc o x o n si g ne d ra n k test will be use d. 
S o me e x pl orat or y e n d p oi nts ma y als o be a nal yze d usi n g a nal ysis of c o varia nce, t- tests, Wilc o x o n 
si g n ra n k test or as des cri pti ve s u m maries. T here will be n o c orrecti o n t o be ma de f or m ulti ple 
c o m paris o ns beca use of t he e x pl orat or y n at ure of t he data.  A n al ysis of cate g orical e x pl orat or y 
e n d p oi nts ma y be perf or me d usi n g c hi- s quare t ests.   
A d diti o nal e x pl orat or y a nal yses ma y be perf or me d t o f urt her st u d y t he effects of t he treat me nt, 
as data warra nt e d. S u b gr o u p a nal yses will be perf or me d if data p er mit.  S u b gr o u p ca n be defi ne d 
b y disease se v erit y ( baseli ne T F C sc or e,  C A N T A B Paire d Ass ociate Lear ni n g or T otal A dj uste d 
Err or Sc or e ), se x ( male/f e male), a g e ( dic h ot o mize d at pretreat me nt me dia n a ge), race ( W hite vs. 
n o n- W hite, His pa nic vs. n o n- His pa nic), a n d/ or ot her gr o u pi n g c o v ariates. 
F or ma n y v aria bles, b ot h a bs ol ute a n d perce nt c h a n ge fr o m pre-treat me nt assess me nts mi g ht be 
perf or me d if data p er mitte d.  All data c ollecte d a n d ca pt ure d i n t he C R F will be i ncl u de d i n data 
listi n gs s orte d b y treat me nt, patie nt, st u d y peri o d a n d ti me p oi nt, or as a p pr o priate.   
 
9. 2.  
Prese nt ati o n of Eff ic ac y Me as ures 
Gra p hical prese ntati o n: 
T he ti me-c o urs e of efficac y meas ur es will be pl otte d f or eac h s u bject f or b ot h peri o ds. T he 
c ha n ge fr o m baseli ne of effica c y meas ures b y peri o d (treat me nt) will be pl otte d via b o x pl ot. T he 
distri b uti o n of differe nce of c ha n ge fr o m bas eli ne b y treat me nt ( nefla ma pi m o d – place b o) will be 
pl otte d eit her via scatter pl ot or b o x pl ot. 
 
Ta b ular pr ese ntati o n: 


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P a ge 2 6  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
T he i n di vi d ual val ues a n d descri pti ve statistics f or efficac y meas ures will be s u m marize d b y 
peri o d/treat me nt a n d b y visit. 
9. 3.  S u bject  Dis p ositi o n  
A ta b ulati o n of s u bject dis p ositi o n will be prese nte d b y treat me nt a n d o verall, i ncl u di n g t he 
n u m ber i n eac h a nal ysis p o p ulati o n, t he n u m ber t hat c o m plete d t he st u d y, t he n u m ber l ost t o 
f oll o w- u p, t he n u m ber t h at wit h dre w pri or t o c o m pleti n g t he st u d y, a n d reas o n(s) f or wit h dra wal. 
9. 4.  Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns a n d vi olati o ns n ote d d uri n g cli nical m o nit ori n g are e ntere d i nt o cli nical 
data base.  I m p orta nt pr ot oc ol de viati o ns t hat c o ul d p ote ntiall y i nfl ue nce st u d y o utc o mes will be 
liste d.  T hese ma y i ncl u d e de viati o ns fr o m i ncl usi o n a n d e xcl usi o n criteria, recreati o nal dr u g us e, 
pr o hi bite d c o nc o mita nt me dicati o ns, i nc orrect treat me nt d osi n g, visit wi n d o wi n g de viati o ns.  
S pecificall y, wi n d o wi n g de viati o ns be y o n d +/- 7 d a ys fr o m t he sc h e d ule d (t ar get) st u d y da y will 
be liste d i n t he pr ot oc ol de viati o n data listi n g.  
9. 5.  Missi n g V al ues  
N o i m p utati o ns f or missi n g efficac y a n d s afet y are pla n ne d.     
S u bjects wit h i nc o m plete data will be i ncl u de d i n a nal yses, c o ntri b uti n g as m uc h as is a vaila ble 
f or a n y gi ve n e n d p oi nt. F or A E, missi n g dates will n ot be i m p ute d; h o we ver, if partial dates are 
a vaila ble, t he y will be us e d t o assess w het her t he A E occ urre d d uri n g t he treat me nt peri o d. 
Missi n g se verities of A Es will be c o nsi dere d i n a n y ta b ulati o ns of A E se verit y.   
9. 6.  S u b gr o u ps  
S u b gr o u ps ma y be defi ne d b y baseli ne disease s e v erit y , ge n der ( male/fe m ale), a ge 
( dic h ot o mize d at pr e-treat me nt me dia n a ge), a n d race ( W hite vs N o n- W hite, His pa nic vers us 
n o n- His pa nic ).  S o me e x pl orat or y o utc o me a n al yses mi g ht be assesse d b y p ost- h oc s u b gr o u ps as 
dictate d b y data.   
9. 7.  C o m pli a nce   
St u d y dr u g c o m plia nce will be assesse d via ta blet c o u nts.  A ta b ulati o n of perce nt c o m plia nce 
will be pr o vi de d, w her e perce nt c o m plia nce will be deri ve d as: 
•  T otal n u m ber of ta blets dis pe nse d mi n us t otal n u m ber ta blets ret ur ne d, di vi de d b y t he 
E X P E C T E D n u m ber of t a blets ( base d o n t he n u m ber of da ys fr o m first d os e t o last 
d ose).    
•  Patie nts w h o d o n ot ha ve t he last d ose date or h a v e missi n g ca ps ule c o u nts of st u d y 
me dicati o n will n ot be i ncl u de d i n t his calc ulati o n of c o m plia nce. 
•  Patie nts wit h a c o m plia nce t hat is calc ul ate d t o be o ver 1 0 0 % will ha ve t h eir 
c o m plia nce set t o 1 0 0 %. 
T he n u m ber ( %) of p atie nts wit h c o m plia nce wit hi n eac h of t he f oll o wi n g i nter vals will be 
deri ve d: 


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 2 7  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
• 
9 5- 1 0 0 % 
• 
9 0- < 9 5 % 
• 
8 5- < 9 0 % 
• 
8 0- < 8 5 % 
• 
7 5- < 8 0 % 
• 
7 0- < 7 5 % 
• 
< 7 0 % 
  
9. 8.  B aseli ne S u bject D at a  a n d Dise ase C h ar acteristics A n al yses  
F or t h ose patie nts missi n g a pre-tr eat me nt val u e ( Da y 1) f or a partic ular para meter, t h e scree ni n g 
val ue ma y be use d as t he baseli ne val ue f or t hat para meter.  
Scree ni n g data, d e m o gra p hic c har acteristics, a n d baseli ne T F C  disease ass ess me nts will be 
prese nte d usi n g s u m mar y statistics b y treat me nt se q ue nce, a n d o verall. 
Baseli ne cate g orical varia bles will be i nfere ntiall y assesse d via a c hi s q uare test, w hile baseli ne 
c o nti n u o us o utc o mes will be i nfere ntiall y ass esse d via Wilc o x o n ra n k s u m test f or t w o 
treat me nts.  Si nce t his is a cr oss o ver st u d y desi g n, o nl y peri o d 1 baseli ne s u bject data will be 
a nal yze d i n t he b aseli ne a nal yses bet w ee n treat me nt gr o u ps.  Me dical hist or y data will be 
ta b ulate d a n d liste d.  
 
 
9. 9.  
Effic ac y A n al yses  
9. 9. 1.  
Pri m ar y Effic ac y A n al ysis 
T he pri mar y efficac y p o p ulati o n will be t he c o m pleter p o p ulati o n.  D u e t o t he n o n-s y m metrical 
nat ure of t he c ha n g e fr o m baseli ne val ues, t he n o n para metri c a p pr o ac h - Wilc o x o n si g ne d ra n k 
test will be use d.  T he pri mar y effi cac y a nal ysis will be perf or me d o n t he pri mar y efficac y 
e n d p oi nt: c ha n ge of lat e n c y d uri n g t he lear ni n g p hase of virt ual M W M ( hi d de n platf or m 
trai ni n g) d uri n g t he nefl a ma pi m o d-treat me nt peri o d c o m pare d t o c h a n ge of t hat d uri n g t he 
place b o- a d mi nistrati o n peri o d. 
Let D i,j  de n ote as t he differe nce of Wee k 1 0 v al ue mi n us t he baseli ne val ue f or it h s u bject at t he 
sa me Peri o d j ( nefl a ma pi m o d or place b o peri o d).   
T heref ore, t he n ot ati o n a n d t he f or m ula f or t h e differe n ce of n efla m a pi m o d peri o d c o m pare d t o 
place b o peri o d i n ter ms of c ha n ge fr o m bas eli ne of late nc y f or it h s u bject is  
θ i, d, = D i, nefl a m a pi m o d - Di, pl a ce b o 
 


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 2 8  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
T he n ull h y p ot hesis is t hat nefla ma pi m o d has n o si g nifica nt dr u g effect o n t he re d ucti o n of 
late nc y; a n d t he alter nati ve h y p ot hesis is t hat nefla ma pi m o d  ca uses a si g nifica nt re d u cti o n of 
late nc y at si g nifica n ce le vel of  = 0. 0 5.   
Wilc o x o n si g ne d ra n k test is e x presse d i n ter ms of me dia n f or differe n ce.  L et θ d be t he 
p o p ulati o n me dia n of differe n ce b et wee n treat me nts ( nefla ma pi o d peri o d mi n us place b o peri o d), 
t he h y p ot heses ar e: 
 
H 0 : θ d = 0  
H a : θ d < 0  
 
9. 9. 2.  
A n al ysis of t he Sec o n d ar y Effic ac y E n d p oi nts 
T he sec o n d ar y efficac y v aria bles are 
•  
Perce nt of ti me s pe nt i n t he c orrect q ua dra nt d uri n g M W M pr o be test d uri n g t he 
nefla ma pi m o d-treat me nt peri o d c o m pare d t o t hat d uri n g t he place b o-a d mi nistrati o n peri o d. 
•  
N u m ber of o verall err ors i n t he C A N T A B paire d ass ociates lear ni n g ( P A L) tas k d uri n g 
t he nefla ma pi m o d-tr eat m e nt peri o d c o m pare d t o t hat d uri n g t he place b o-a d mi nistrati o n peri o d. 
Let t he deri ve d p ara m eter θ d be t he p o p ulati o n mea n/ me dia n of differe n ce of sec o n dar y efficac y 
para meter bet w ee n treat me nts ( nefla ma pi m o d peri o d mi n us place b o peri o d) as defi ne d i n Secti o n 
9. 9. 1.  Paire d t-test will be use d t o test t he mea n differe nce if t he tar g et metric is s y m metrical at 
mi ni mal .  Ot her wise, t he n o n para metri c a p pr o ac h - Wilc o x o n si g ne d ra n k t est will be use d t o test 
t he me dia n differe nce as State d i n Secti o n 9. 9. 1. T he alter nati ve h y p ot h esis f or testi n g t he 
differe n ce of ( 1) p erce nt of ti me s pe nt i n t he c orrect q ua dra nt d uri n g M W M pr o be is H a : θ d > 0  
a n d ( 2) C A N T A B P A L is H a : θ d < 0 at si g nifica nce le vel of  = 0. 0 5. 
Data will be ta b ulate d b y visit a n d b y treat me nt. A d diti o nal e x pl orat or y a nal yses, as state d i n 
Secti o n 9. 1, ma y be perf or me d t o f urt her st u d y t h e effects of t he treat me nt gi ve n data warra nt e d. 
 
9. 9. 3.  
A n al ysis of t he e x pl or at or y Effic ac y E n d p oi nts 
T he e x pl orat or y effi cac y meas ures are t he f ull set of para m eters i n t he C A N T A B assess me nts :  
M ot or Scree ni n g Tas k ( M O T) 
Reacti o n Ti me ( R TI) 
Paire d Ass ociate L ear ni n g ( P A L) 
S patial S pa n ( S S) 
O ne T o uc h St oc ki n gs of Ca m bri d ge ( O T S) 
S patial Rec o g niti o n Me m or y ( S R M) 


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C o nfi de nti al  
 
 
Patter n Rec o g niti o n Me m or y ( P R M) 
Descri pti ve a n al yses will be perf or me d t o descri be t he f ull set of para meters i n t he C A N T A B 
assess me nt.  
A d diti o nal e x pl orat or y a n d s u b gr o u p a nal yses, as state d i n Secti o n 9. 1, ma y be perf or me d t o 
f urt her st u d y t he effects of t he treat me nt as di ctat e d b y data. 
 
Q uesti o n:  D o y o u wa nt t o me nti o ne d ot her Virt ual M W M para meters (tra vel pa t h le n gt hs, q ua dra nt d well 
ti mes, etc.) as e x pl orat or y efficac y e n d p oi nts  here ? 
9. 9. 4.  
A n al ysis of Pl as m a Bi o m ar kers 
T here is n o bi o mar k er a n al ysis pla n ne d. 
 
9. 9. 5.  
S u m m ar y of Re as o ns f or Effic ac y N o n-e v al u a bilit y/ E xcl usi o n fr o m Effic ac y 
A n al yses 
All n o n-e val ua ble or e xcl usi o n val ues fr o m efficac y a nal yses will be liste d a n d ta b ulate d b y 
st u d y visit a n d b y treat me nt. 
 
9. 1 0.  
P h ar m ac o ki netic A n al ysis  
T here is n o p har mac o ki n etic a nal ysis pla n ne d. 
 
9. 1 1.  
S afet y a n d T oler a bilit y A n al yses  
9. 1 1. 1.  
Ge ner al S afet y A n al ysis Met h o ds 
Safet y a n d t oler a bilit y will be e val uate d usi n g des cri pti ve statistics a n d listi n gs of a d vers e e ve nts, 
cli nical safet y la b orat or y test val ues, vital si g ns, wei g ht, b o d y te m perat ure, E C Gs a n d ot her 
safet y par a meters. Safet y o utc o mes will be prese nt e d f or t he safet y p o p ulati o n.   
A nal yses of A Es will be perf or me d f or t h ose e ve nts t hat are c o nsi dere d treat me nt e mer ge nt, 
w here tr eat me nt e mer ge nt is defi ne d as a n y A E wit h o nset ( or w orse ni n g of a pre-e xisti n g 
c o n diti o n) after t he first d ose of treat me nt.  A d v erse e ve nts wit h partial dat es will be assesse d 
usi n g t he a vaila ble date i nf or mati o n t o deter mi ne treat me nt-e mer ge nt stat us. A d verse e ve nts wit h 
c o m pletel y missi n g dates will be ass u me d t o be treat me nt e mer ge nt. 
A d verse e ve nts will be s u m marize d b y visit a n d treat me nt, usi n g s u bject i nci de nce rates; 
t heref or e, i n a n y ta b ulati o n, a s u bject c o ntri b utes o nl y o nce t o t he c o u nt f or a gi ve n A E 
( pref err e d ter m) p er treat me nt.  Se parate ta b ul ati o ns will be pr o d uce d f or all T E A Es, treat me nt-
relate d A Es (t h ose c o nsi dere d b y t he i n vesti gat or as p ossi bl y st u d y dr u g relate d), S A Es, a n d 
disc o nti n uati o ns d ue t o A Es.  B y s u bject listi n gs will be pr o vi de d f or a n y deat hs, S A Es, a n d A Es 
lea di n g t o disc o nti n uati o n of treat me nt. 


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 0  of 5 0  
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C o nfi de nti al  
 
 
N o f or mal h y p ot hesis testi n g of A E i nci de nce rates will be perf or me d. 
9. 1 1. 2.  
R o uti ne La b orat or y D ata 
F or place b o a n d n efla ma pi m o d treat me nt gr o u ps, t he act ual val ue a n d c h a n ge fr o m baseli ne t o 
eac h o n-st u d y e val uati o n will be s u m marize d f or eac h cli nical la b orat or y p ara meter.  Cli nicall y 
si g nifica nt la b orat or y v al ues ma y be prese nte d i n a se parate dat a listi n g.   
9. 1 1. 3.  
Vital Si g ns a n d P h ysical E xa mi nati o n 
Act ual val ues a n d c ha n g es fr o m baseli ne t o eac h o n-st u d y e val uati o n will be s u m marize d b y visit 
a n d treat me nt f or vital si g ns.  P h ysical e xa mi nati o n fi n di n gs will be ta b ulate d a n d s u m marize d 
b y visit a n d treat me nt.  T he n u m ber of s u bjects wit h p ote ntiall y cli nicall y si g nifica nt ( P C S) 
c ha n ges i n vital si g ns will be ta b ulate d.  P ote ntiall y cli nicall y si g nifica nt t hres h ol ds will be 
defi ne d pri or t o br ea ki n g t he st u d y bli n d. 
9. 1 1. 4.  
Electr ocar di o gra m E v al uati o ns 
Electr ocar di o gra m o utc o mes will be s u m marize d descri pti vel y b y visit a n d b y treat me nt.  
C orrecte d Q T will be cal c ulate d usi n g Fri d ericia’s c orrecti o n.  T he n u m ber of s u bjects wit h P C S 
c ha n ges i n E C G i nter v als will be ta b ulate d.  T he P C S t hres h ol ds will be defi ne d pri or t o 
brea ki n g t he st u d y bli n d. 
9. 1 1. 5.  
C o nc o mita nt Me dicati o ns  
C o nc o mita nt me dicati o ns will be s u m marize d b y W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y 
A nat o mical- T hera pe utic- C he mical classificati o n a n d preferre d t er m.  C o nc o mita nt me dicati o ns 
i nf or mati o n will be ta b ulate d a n d s u m marize d b y visit a n d b y treat me nt. 
9. 1 1. 6.  
St u d y Ter mi nati o n Stat us 
St u d y ter mi nati o n stat us will be ta b ulate d a n d s u m marize d b y visit a n d b y treat me nt. 
 


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 1  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 0.  
R E F E R E N C E  
Fra y PJ, R o b bi ns T W. C A N T A B batter y: Pr o p ose d utilit y i n ne ur ot o xic ol o g y. Ne ur ot oxic ol o gy 
a n d Ter at ol o gy  1 9 9 6; 1 8( 4): 4 9 9- 5 0 4. 
H u nti n gt o n St u d y Gr o u p. U nifie d H u nti n gt o n’s Disease Rati n g Scale: relia bilit y a n d c o nsiste nc y. 
M o v Dis 1 9 9 6; 1 1( 2): 1 3 6- 1 4 2. 
M orris R. De vel o p me nts of a water- maze pr o ce d ure f or st u d yi n g s patial lear ni n g i n t he rat. J 
Ne ur osci Met h o ds  1 9 8 4; 1 1: 4 7 – 6 0. 
O we n et al. Vis u o-s p atial s h ort-ter m rec o g niti o n me m or y a n d lear ni n g aft er te m p oral l o be 
e xcisi o ns, fr o ntal l o be e x cisi o ns or a m y g dal o- hi p p oca m pect o m y i n ma n. Ne ur o psyc h ol o gi a  
1 9 9 5; 3 3( 1): 1- 2 4. 
P os ner K et al. T he C ol u m bia- S uici de Se verit y Rati n g Scale: i nitial vali dit y a n d i nter nal 
c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h a d olesce nts a n d a d ults. A m J Psyc hi atry  
2 0 1 1; 1 6 8: 1 2 6 6- 1 2 7 7. 
Zi g m o n d A S, S nait h R P. T he h os pital a n xiet y a n d de pressi o n scal e. Act a Ps yc hi atr Sc a n d  
1 9 8 3; 6 7( 6): 3 6 1- 7 0. 


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P a ge 3 2  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 1.  
A P P E N DI X  
 
1 1. 1.  
T a ble of C o nte nts f or D at a Dis pl a y S pecific ati o ns  
T he n u m beri n g of ta bles, data listi n gs, a n d fi g ures will be c o nsiste nt wit h t he I C H E 3 g ui da nce. 
1 1. 1. 1.  
List of T a bles 
Ta bles ar e di vi de d i nt o 4 secti o ns:  St u d y c haracteristics, efficac y, safet y, a n d p har mac o ki netic 
prese ntati o ns. 
• 
Ta bles i n t he 1 4. 1. X seri es are st u d y c haracteristi cs, i.e., patie nt dis p ositi o n a n d 
baseli ne c haracteristics ta b ulati o ns. 
• 
Ta bles i n t he 1 4. 2. X seri es are effi cac y- base d d a t a. 
• 
Ta bles i n t he 1 4. 3. X seri es are s afet y- b ase d d ata. 
 
Title  
P o p ul ati o n  
1 4. 1 St u d y P o p ul ati o n Secti o n  
1 4. 1. 1  
S u m mar y of S u bject Dis p ositi o n  
Ra n d o mize d  
1 4. 1. 2  
S u m mar y of A nal ysis P o p ulati o ns  
Safet y; E E P  
1 4. 1. 3  
De m o gra p hics a n d Baseli ne C haracteristics  
Safet y; E E P  
1 4. 1. 3. 1  
S u m mar y of De m o gra p hic C haracteristics  
Safet y; E E P  
1 4. 1. 3. 2  
S u m mar y of Baseli ne/ P h ysical E xa mi nati o ns 
C h aracteristics  
Safet y; E E P  
1 4. 1. 4  
Me dical Hist or y a n d Pri or Me dicati o ns  
Safet y  
1 4. 1. 5  
Maj or De viati o ns  
Ra n d o mize d  
1 4. 2 Effic ac y Secti o n  
  
1 4. 2. 1 Pri mar y Efficac y E n d p oi nt   
E E P  
1 4. 2. 1. 1  
S u m mar y of Late nc y of Virt ual M W M b y Visit, b y 
Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 1. 2  
S u m mar y of C ha n ges of Late nc y of Virt ual M W M 
b y Visit, b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 1. 3  
S u m mar y of differe nce of C ha n ges of Late nc y of 
Virt ual M W M at e n d of peri o d ( nefla ma pi m o d 
peri o d - Place b o peri o d)  
E E P  
1 4. 2. 2 Sec o n dar y Efficac y E n d p oi nts   
  
1 4. 2. 2. 1  
S u m mar y of perce nt of ti me s pe nt i n t he c orrect 
q ua dra nt d uri n g M W M pr o be test b y Visit b y Peri o d 
a n d b y Treat me nt  
E E P  


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 3  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 2. 2  
S u m mar y of c ha n ge of perce nt of ti me s pe nt i n t he 
c orrect q ua dra nt d uri n g M W M pr o be test (at e n d of 
t he peri o d - at t he be gi n ni n g of t he peri o d) b y Peri o d 
a n d b y Treat me nt  
E E P  
1 4. 2. 2. 3  
S u m mar y of differe nce of c ha n ge of perce nt of ti me 
s pe nt i n t he c orrect q ua dra nt d uri n g M W M pr o be test 
( nefla ma pi m o d peri o d - Place b o peri o d)  
C P  
1 4. 2. 2. 4  
S u m mar y of n u m ber of o verall err or i n t he 
C A N T A B paire d ass ociates le a ni n g tas k b y Visit b y 
Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 2. 5  
S u m mar y of c ha n ge of n u m ber of o verall err or i n t he 
C A N T A B paire d ass ociates le a ni n g tas k (at e n d of 
t he peri o d - at t he be gi n ni n g of t he peri o d) b y Peri o d 
a n d b y Treat me nt  
E E P  
1 4. 2. 2. 6  
S u m mar y of differe nce of c ha n ge of n u m ber of 
o verall err or i n t he C A N T A B paire d ass ociates 
lea ni n g tas k ( nefla ma pi m o d peri o d - Place b o peri o d)  
C P  
1 4. 2. 3 E x pl orat or y Efficac y E n d p oi nts   
  
1 4. 2. 3. 1  
S u m mar y of C A N T A B M ot or Scree ni n g Tas k 
( M O T) b y visit, b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 2  
S u m mar y of C ha n ges of C A N T A B M ot or Scree ni n g 
Tas k ( M O T) b y visit, b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 3  
S u m mar y of C A N T A B Reacti o n Ti me ( R TI) b y 
visit, b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 4  
S u m mar y of C ha n ges of Reacti o n Ti me ( R TI) b y 
visit, b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 5  
S u m mar y of C A N T A B Paire d Ass ociate Lear ni n g 
( P A L) b y visit, b y Peri o d a n d b y Treat me nt 
E E P  
1 4. 2. 3. 6  
S u m mar y of C ha n ges of Paire d Ass ociate Lear ni n g 
( P A L) b y visit, b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 7  
S u m mar y of C A N T A B S patial S pa n ( S S) b y visit, b y 
Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 8  
S u m mar y of C ha n ges of S patial S pa n ( S S) b y visit, 
b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 9  
S u m mar y of C A N T A B O ne T o uc h St oc ki n gs of 
Ca m bri d ge ( O T S) b y visit, b y Peri o d a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 1 0  
S u m mar y of C ha n ges of O ne T o uc h St oc ki n gs of 
Ca m bri d ge ( O T S) b y visit, b y Peri o d a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 1 1  
S u m mar y of C A N T A B S patial Rec o g niti o n Me m or y 
( S R M) b y visit, b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 1 2  
S u m mar y of C ha n ges of S patial Rec o g niti o n 
Me m or y ( S R M) b y visit, b y Peri o d a n d b y Treat me nt  
E E P  
1 4. 2. 3. 1 3  
S u m mar y of C A N T A B Patter n Rec o g niti o n Me m or y 
( P R M) b y visit, b y Peri o d a n d b y Treat me nt 
E E P  
1 4. 2. 3. 1 4  
S u m mar y of C ha n ges of Patter n Rec o g niti o n 
Me m or y ( P R M) b y visit, b y Peri o d a n d b y Treat me nt  
E E P  


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 4  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 3. 1 5 
- 
1 4. 2. 3. x x  
ot her Virt ual M W M para meters (tra vel pat h le n gt hs, 
q ua dra nt d well ti mes, etc.) - T B D  
E E P  
1 4. 3 S afet y D at a  
1 4. 3. 1  
S u m mar y of  Dr u g C o u nt  t o nefla ma pi m o d b y 
Treat me nt a n d b y Visit  
Safet y  
1 4. 3. 2. 1  
S u m mar y of A d verse E ve nts b y Treat me nt a n d b y 
Visit  
Safet y  
1 4. 3. 2. 2  
S u m mar y of Deat h a n d Seri o us A d verse E ve nts b y 
Treat me nt a n d b y Visit  
Safet y  
1 4. 3. 2. 3  
S u m mar y of Dr u g -Relate d A d verse E ve nts b y 
Treat me nt Gr o u p  
Safet y  
1 4. 3. 3  
Listi n g of S u bjects W h o Beca me Pre g na nt D uri n g 
t he St u d y 
Safet y  
1 4. 3. 4  
S u m mar y of Act ual Val ues a n d C ha n ges fr o m 
Baseli ne i n Cli nical C he mistr y Data b y Treat me nt 
Gr o u p a n d b y Visit  
Safet y  
1 4. 3 . 5 
S u m mar y of Act ual Val ues a n d C ha n ges fr o m 
Baseli ne i n He mat ol o g y Data b y Treat me nt Gr o u p 
a n d b y Visit 
Safet y  
1 4. 3. 6  
S u m mar y of Act ual Val ues a n d C ha n ges fr o m 
Baseli ne i n Vital Si g ns b y Treat me nt Gr o u p a n d b y 
Visit  
Safet y  
1 4. 3. 7  
S u m mar y of E C G Data  
Safet y  
1 4. 3. 8  
S u m mar y of C o nc o mita nt Me dicati o n  
Safet y  
 
 
1 1. 1. 2.  
List of Fi g ures 
Title  
P o p ul ati o n  
1 4. 2 Fi g ure f or Effic a c y D at a 
  
1 4. 2. 1 
Fi g ure Pri m ar y Effic ac y E n d p oi nt 
  
1 4. 2. 1. 1  
Pri mar y Efficac y E n d p oi nt ( Late nc y of Virt ual 
M W M) Ti me Pr ofile Pl ot b y I n di vi d ual a n d b y 
Treat me nt  
E E P  
1 4. 2. 1. 2  
Mea n C ha n ge ( + S D) of Pri mar y Efficac y E n d p oi nt 
( Late nc y of Virt ual M W M) Ti me Pr ofile Pl ot fr o m 
Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 1. 3  
B o x pl ot Pri mar y Efficac y E n d p oi nt ( Late nc y of 
Virt ual M W M) C ha n ge fr o m Baseli nes Val ues b y 
Treat me nt b y Visit  
E E P  


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 5  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 1. 4  
B o x pl ot C ha n ges of Pri mar y Efficac y E n d p oi nt 
( Late nc y of Virt ual M W M) Val ues fr o m Baseli nes 
b y Treat me nt b y Visit  
E E P  
1 4. 2. 2 
Fi g ure f or Sec o n d ar y Effic ac y E n d p oi nt 
  
1 4. 2. 2. 1  
perce nt of ti me s pe nt i n t he c orrect q ua dra nt d uri n g 
M W M pr o be test - Ti me Pr ofile Pl ot b y I n di vi d ual 
a n d b y Treat me nt 
E E P  
1 4. 2. 2. 2  
Mea n C ha n ge ( + S D) of perce nt of ti me s pe nt i n t he 
c orrect q ua dra nt d uri n g M W M pr o be test - Ti me 
Pr ofile Pl ot fr o m Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 2. 3  
B o x pl ot perce nt of ti me s pe nt i n t he c orrect q ua dra nt 
d uri n g M W M pr o be test - C ha n ge fr o m Baseli nes 
Val ues b y Treat me nt b y Visit  
E E P  
1 4. 2. 2. 4  
B o x pl ot C ha n ges of perce nt of ti me s pe nt i n t he 
c orrect q ua dra nt d uri n g M W M pr o b e test Val ues 
Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 2. 5  
n u m ber of o verall err or  i n t he C A N T A B paire d 
ass ociates lea ni n g tas k Ti me Pr ofile Pl ot b y 
I n di vi d ual a n d b y Treat me nt 
E E P  
1 4. 2. 2. 6  
Mea n C ha n ge ( + S D) of n u m ber of o verall err or i n 
t he C A N T A B paire d ass ociates lea ni n g tas k Ti me 
Pr ofile Pl ot fr o m Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 2. 7  
B o x pl ot n u m ber of o verall err or i n t he C A N T A B 
paire d ass ociates lea ni n g tas k C ha n ge fr o m Baseli nes 
Val ues b y Treat me nt b y Visit  
E E P  
1 4. 2. 2. 8  
B o x pl ot C ha n ges of n u m ber of o verall err or  i n t he 
C A N T A B paire d ass ociates le a ni n g tas k fr o m 
Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 3 
Fi g ure f or E x pl or at or y Effic ac y E n d p oi nt 
  
1 4. 2. 3. 1  
C A N T A B M ot or Scree ni n g Tas k ( M O T) Ti me 
Pr ofile Pl ot b y I n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 3. 2  
Mea n C ha n ge ( + S D) of C A N T A B M ot or Scree ni n g 
Tas k ( M O T) Ti me Pr ofile Pl ot fr o m Baseli nes b y 
Treat me nt b y Visit  
E E P  
1 4. 2. 3. 3  
B o x pl ot C A N T A B M ot or Scree ni n g Tas k ( M O T) 
C h a n ge fr o m Baseli nes Val ues b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 4  
B o x pl ot C A N T A B M ot or Scree ni n g Tas k ( M O T) 
Val ues Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 5  
C A N T A B Reacti o n Ti me ( R TI) Ti me Pr ofile Pl ot b y 
I n di vi d ual a n d b y Treat me nt 
E E P  


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 6  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 3. 6  
Mea n C ha n ge ( + S D) of C A N T A B Reacti o n Ti me 
( R TI) Ti me Pr ofile Pl ot fr o m Baseli nes b y Treat me nt 
b y Visit  
E E P  
1 4. 2. 3. 7  
B o x pl ot C A N T A B Reacti o n Ti me ( R TI) C ha n ge 
fr o m Baseli nes Val ues b y Treat me nt b y Visit 
E E P  
1 4. 2. 3. 8  
B o x pl ot C A N T A B Reacti o n Ti me ( R TI) Val ues 
Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 9  
C A N T A B Paire d Ass ociate L ear ni n g ( P A L) Ti me 
Pr ofile Pl ot b y I n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 3. 1 0  
Mea n C ha n ge ( + S D) of C A N T A B Paire d Ass ociate 
Lear ni n g ( P A L) Ti me Pr ofile Pl ot fr o m Baseli nes b y 
Treat me nt b y Visit  
E E P  
1 4. 2. 3. 1 1  
B o x pl ot C A N T A B Paire d Ass ociate Lear ni n g ( P A L) 
C h a n ge fr o m Baseli nes Val ues b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 1 2  
B o x pl ot C A N T A B Paire d Ass ociate Lear ni n g ( P A L) 
Val ues Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 1 3  
C A N T A B S patial S pa n ( S S) Ti me Pr ofile Pl ot b y 
I n di vi d ual a n d b y Treat me nt 
E E P  
1 4. 2. 3. 1 4  
Mea n C ha n ge ( + S D) of C A N T A B S patial S pa n ( S S) 
Ti me Pr ofile Pl ot fr o m Baseli nes b y Treat me nt b y 
Visit  
E E P  
1 4. 2. 3. 1 5  
B o x pl ot C A N T A B S patial S pa n ( S S) C ha n ge fr o m 
Baseli nes Val ues b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 1 6  
B o x pl ot C A N T A B S patial S pa n ( S S) Val ues 
Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 1 7  
C A N T A B O ne T o uc h St oc ki n gs of Ca m bri d ge 
( O T S) Ti me Pr ofile Pl ot b y I n di vi d ual a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 1 8  
Mea n C ha n ge ( + S D) of C A N T A B O ne T o uc h 
St oc ki n gs of Ca m bri d ge ( O T S) Ti me Pr ofile Pl ot 
fr o m Baseli nes b y Treat me nt b y Visit 
E E P  
1 4. 2. 3. 1 9  
B o x pl ot C A N T A B O ne T o uc h St oc ki n gs of 
Ca m bri d ge ( O T S) C ha n ge fr o m Baseli nes Val ues b y 
Treat me nt b y Visit  
E E P  
1 4. 2. 3. 2 0  
B o x pl ot C A N T A B O ne T o uc h St oc ki n gs of 
Ca m bri d ge ( O T S) Val ues Baseli nes b y Treat me nt b y 
Visit  
E E P  
1 4. 2. 3. 2 1  
C A N T A B S patial Rec o g niti o n Me m or y ( S R M) Ti me 
Pr ofile Pl ot b y I n di vi d ual a n d b y Treat me nt  
E E P  


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 7  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 3. 2 2  
Mea n C ha n ge ( + S D) of C A N T A B S patial 
Rec o g niti o n Me m or y ( S R M) Ti me Pr ofile Pl ot fr o m 
Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 2 3  
B o x pl ot C A N T A B S patial Re c o g niti o n Me m or y 
( S R M) C ha n ge fr o m Baseli nes Val ues b y Treat me nt 
b y Visit  
E E P  
1 4. 2. 3. 2 4  
B o x pl ot C A N T A B S patial Re c o g niti o n Me m or y 
( S R M) Val ues Baseli nes b y Treat me nt b y Visit 
E E P  
1 4. 2. 3. 2 5  
C A N T A B Patter n Rec o g niti o n Me m or y ( P R M) Ti me 
Pr ofile Pl ot b y I n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 3. 2 6  
Mea n C ha n ge ( + S D) of C A N T A B Patter n 
Rec o g niti o n Me m or y ( P R M) Ti me Pr ofile Pl ot fr o m 
Baseli nes b y Treat me nt b y Visit  
E E P  
1 4. 2. 3. 2 7  
B o x pl ot C A N T A B Patter n Rec o g niti o n Me m or y 
( P R M) C ha n ge fr o m Baseli nes Val ues b y Treat me nt 
b y Visit  
E E P  
1 4. 2. 3. 2 8  
B o x pl ot C A N T A B Patter n Rec o g niti o n Me m or y 
( P R M) Val ues Baseli nes b y Treat me nt b y Visit 
E E P  
1 4. 2. 3. 2 9 - 
1 4. 2. 3. x x  
ot her e x pl orat or y Virt ual M W M para meters (tra vel 
pat h le n gt hs, q ua dra nt d well ti mes, etc.) - T B D  
E E P  


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 8  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 1. 1. 3.  
Listi n gs  
 
Title  
P o p ul ati o n  C o m m e nt  
1 6. 2. 1. 1  
S u bject E nr oll me nt I nf or mati o n  
E nr olle d   
  
1 6. 2. 1. 2  
S u bject Dis p ositi o n  
Safet y   
  
1 6. 2. 2. 1  
S u bjects w h o di d n ot Satisf y I ncl usi o n/ E xcl usi o n Criteria (if 
a p plica ble) 
Scree ni n g 
Fail ure  
  
1 6. 2. 2. 2  
Pr ot oc ol De viati o ns  
Safet y   
  
1 6. 2. 4. 1  
S u bject De m o gra p hic a n d Baseli ne C haracteristics  
Safet y   
  
1 6. 2. 4. 2  
Listi n g of Me dical Hist or y  
Safet y   
  
1 6. 2. 4. 3  
Listi n g of P h ysical E xa m  
Safet y   
  
1 6. 2. 4. 4  
Listi n g of C o nc o mita nt Me dicati o ns  
Safet y   
  
1 6. 2. 5. 1  
Listi n g of Dr u g A d mi nistrati o n  
Safet y   
  
1 6. 2. 6. 1  
Listi n g of Relati o ns hi p of A d verse E ve nt B o d y S yste ms, Gr o u p 
Ter ms, a n d Ver bati m Te xt  
Safet y   
  
1 6. 2. 6. 2  
Listi n g of All A d verse E ve nts  
Safet y   
  
1 6. 2. 6. 3  
Listi n g of S u bjects Wit h dra w n D ue t o A Es  
Safet y   
  
1 6. 2. 6. 4  
Listi n g of Deat hs or S A Es (if a n y)  
Safet y   
  
1 6. 2. 7. 1  
Listi n g of He mat ol o g y Data  
Safet y   
  


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 3 9  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 6. 2. 7. 2  
Listi n g of Cli nical C he mistr y Data  
 Safet y   
  
1 6. 2. 7. 3  
Listi n g of Uri nal ysis  
Safet y  
if 
a p plica ble 
1 6. 2. 8.  
Listi n g of Vital Si g n Data  
Safet y   
  
1 6. 2. 9.  
Listi n g of E C G Data  
Safet y   
  
 
 


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 4 0  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 1. 2.  
S a m ple T a ble Te m pl ate  


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 4 1  of 5 0  
 
 
1 1. 2. 1.  
S a m ple Te m pl ate f or C o u nt  D at a  
T a bl e 1 4. x. x. x: S u m m ar y of C o u nt s b y vi sit a n d b y Tr e at m e nt  
P o p ul ati o n  
n  
Tr e at m e nt  
Vi sit 1  
Vi sit 2  
Vi sit 3  
Vi sit 4  
Vi sit 5  
R a n d o mi z e d 
( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0  m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
  
S af et y ( N = x)  
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0  m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %) 
  
 
 
 
 
 
 
  
E E P  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0  m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
  
C o m pl et er  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %) 
N ot e: P er c e nt a g e s ar e b a s e d o n t h e t ot al n u m b er of s u bj e ct s i n e a c h tr e at m e nt gr o u p of t h e s a m e p o p ul ati o n  
 
 
 


EI P 1 9 -N F D -4 0 1, Versi o n 1  2 0 1 9  
P a ge 4 2  of 5 0  
 
 
 
T a bl e 1 4. x. x. x: S u m m ar y of Effi c a c y/ S af et y/ L a b C o u nt D at a b y vi sit a n d b y Tr e at m e nt  
  
  
  
F or E x a m pl e: Diff er e n c e of Effi c a c y  S c or e fr o m B a s eli n e  
Vi sit  
n  
Tr e at m e nt  
≤-2  
-1  
± 0  
+ 1  
+ 2  
≥ 3  
Vi sit 1  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
 
  
Vi sit 2  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %) 
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
 
  
Vi sit 3  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
 
  
Vi sit 4  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
 
  
F oll o w -u p  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
N ot e: P er c e nt a g e s ar e b a s e d o n t h e t ot al n u m b er of s u bj e ct s i n e a c h tr e at m e nt gr o u p of t h e s a m e vi sit  


EI P 1 9 -N F D -4 0 1, Versi o n 1 , 2 0 1 9 
P a ge 4 3  of 5 0  
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
4 3  
 
 
  
 
1 1. 2. 2.  
S a m ple Te m pl ate f or C o nti n u o us D at a ( Effic ac y / S afet y/ L a b) 
 
T a bl e 1 4. x. x. x : S u m m ar y of E n d p oi nt b y V i sit a n d b y Tr e at m e nt 
Vi sit  
Tr e at m e nt  
Mi n.  
Q 1  
M e di a n  
M e a n  
Q 3  
M a x.  
N  
s d  
S cr e e ni n g  
Pl a c e b o  
  
  
  
  
  
  
  
  
4 0 m g  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
  
Vi sit 1  
Pl a c e b o  
  
  
  
  
  
  
  
  
 
4 0 m g  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Vi sit 2  
Pl a c e b o  
 
 
 
 
 
 
 
 
 
4 0 m g