Clinical trial NCT03093324
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: RRMS Multiple Sclerosis MS Alkermes ALKS 8700 Dimethyl Fumarate DMF Tecfidera
Sponsor: Biogen
Start date: 2017-03-15; Completion date: 2019-06-27
Enrollment: 506 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are to evaluate the utility of two gastrointestinal (GI) symptom scales (Individual GI Symptom and Impact Scale {IGISIS} and Global GI Symptom and Impact Scale {GGISIS}) in assessing GI tolerability in adult subjects with RRMS after administration of ALKS 8700 or Dimethyl Fumarate (DMF) in Part A, to compare the GI tolerability of ALKS 8700 and DMF in adult subjects with RRMS using IGISIS and GGISIS in Part B, and to Evaluate the safety and tolerability of ALKS 8700 in adult subjects with RRMS in Parts A and B.

Detailed description:

Arms: arm 1: Oral capsules, administered orally twice daily. arm 2: Oral capsules, administered orally twice daily.
Interventions: intervention 1: ALKS 8700 intervention 2: Dimethyl Fumarate
Intervention descriptions: intervention 1: Administered as specified in the treatment arm. intervention 2: Administered as specified in the treatment arm.

Protocol documents:
Prot_000.pdf: 
 
C LI NI C A L  ST U D Y P R O T O C O L 
A L K 8 7 0 0 - A3 0 2  / N C T 0 3 0 9 3 3 2 4
St u d y  Titl e :   
A  P h as e  3  St u d y i n  S u bj e cts   wit h   R el a psi n g   R e  mitti n g 
M ulti pl e  S cl er osis t o  E v al u at e t h e  T ol er a bilit y  of 
A L  K S    8 7 0 0  a n d   Di  m et h yl  F u  m ar at e 
D o c u  m e nt   D at e  :   
v  2. 0 (i n c or p or at es   A  m e n d  m e nt  1. 0 ): 1 5   D e c  2 0 1 6 
Ori gi n al  Pr ot o c ol:   0 8  F e b  2 0 1 6 
S p o ns or:   
Al k er  m es, I n c.   
8 5 2   Wi nt er  Str e et 
W alt h a  m,   M  A  0 2 4 5 1 
U S  A   
C  O  N FI  D  E  N  TI  A  L    
I nf or  m ati o n  a n d  d at a i n t his  pr ot o c ol  c o nt ai n tr a d e s e cr ets  a n d  pri vil e g e d  or  c o nfi d e nti al i nf or  m ati o n, 
w hi c h is t h e  pr o p ert y  of     Al k er  m es, I n c.   N o  p ers o n is  a ut h ori z e d t o   m a k e it  p u bli c   wit h o ut t h e   writt e n 
p er  missi o n  of   Al k er  m es, I n c.  T h es e r estri cti o ns  or  dis cl os ur es   will  a p pl y  e q u all y t o  all f ut ur e i nf or  m ati o n 
s u p pli e d t o  y o u t h at is i n di c at e d  as  pri vil e g e d  or  c o nfi d e nti al.  




 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  3  of  6 7 
2.    
S  Y  N  O P SI S  
N a  m e  of  S p o ns o r/  C o  m p a n y:   Al k er  m es, I n c.   
N a  m e  of I n v esti g ati o n al  P r o d u ct:   A L  K  S  8 7 0 0  
N a  m e  of   A cti v e I n g r e di e nt:   A L  K S  8 7 0 0   
Titl e  of   S t u d y: A  P h as e  3  St u d y i n  S u bj e cts   wit h   R el a psi n g   R e  mitti n g   M ulti pl e  S cl er osis t o  E v al u at e 
t h e  T ol er a bilit y of   A L  K S  8 7 0 0  a n d   Di  m et h yl  F u  m ar at e  
I n v esti g at o rs:  T his st u d y   will  b e  a   m ulti c e nt er st u d y . 
St u d y  P e ri o d:   
Esti  m at e d  d at e  of first  su bj e ct’s  c o ns e nt:  Q 1  2 0 1 7 
Esti  m at e d  d at e  of l ast s u bj e ct’s  l ast  visit: Q 4   2 0 1 8  
P h as e  of   D e v el o p  m e nt:  3 
O bj e cti v es  :  
•  
E v al u at e t h e  utilit y  of t  w o   GI s y  m pt o  m s c al es (I  GI SI S  a n d   G  GI SI S)  a n d  e n d p oi nts  d eri v e d 
fr o  m t h e s c al es i n  ass essi n g   GI t ol er a bilit y i n  a d ult s u bj e cts   wit h r el a psi n g r e  mitti n g 
m ulti pl e s cl er osis   (R  R  M S  ) (aft er  a d  mi nistr ati o n  of   A L  K S  8 7 0 0  or   D  M F i n  P art   A  
•  
C o  m p ar e t h e   GI t ol er a bilit y  of   A L  K S  8 7 0 0  a n d   D  M F i n  a d ult s u bj e cts   wit h   R  R  M S  usi n g 
t  w o   GI s y  m pt o  m s c al es (I  GI SI S  a n d   G  GI SI S) i n  P art   B   wit h  e n d p oi nts i nf or  m e d fr o  m 
P art    A 
•  
E v al u at e t h e s af et y  a n d t ol er a bilit y  of   A L  K S  8 7 0 0 i n  a d ult s u bj e cts   wit h   R  R  M S i n  P arts   A 
a n d   B 
M et h o d ol o g y   ( P a rt   A  a n d  P a rt   B): T his is  a r a n d o  mi z e d,  d o u bl e -bli n d,   m ulti c e nt er st u d y i n  a d ult 
s u bj e cts   wit h   R  R  M S  c o n d u ct e d i n t  w o  p arts ( P arts   A  a n d   B).  T h e st u d y  d esi g n is  a n  a d a pti v e  a p pr o a c h 
w h er e  d at a fr o  m  P art   A  c a n  b e  us e d t o   m o dif y t h e   GI t ol er a  bilit y  e n d p oi nt(s) i n  P art   B. 
B ot h  P arts   A  a n d   B  ar e i d e nti c al i n st u d y  d esi g n  a n d i n cl u d e  a  5-  w e e k,  d o u bl e- bli n d tr e at  m e nt  p eri o d 
wit h t  w o  bli n d e d tr e at  m e nt  ar  ms (  A L  K S  8 7 0 0  a n d   D  M F).  P art   A is  e x pl or at or y  a n d  P art   B is 
c o nfir  m at or y.  T h e first  1 2 0  eli gi bl e  s u bj e cts   will  b e r a n d o  mi z e d t o  o n e  of t h e t  w o tr e at  m e nt  gr o u ps i n 
P art   A ( n = 6 0  p er  gr o u p).   O n c e t h e r a n d o  mi z ati o n f or  P art   A is  c o  m pl et e, t h e  n e xt  3 0 0  eli gi bl e s u bj e cts 
will  b e r a n d o  mi z e d i nt o  o n e  of t h e t  w o tr e at  m e nt  gr o u ps i n  P art   B ( n = 1 5 0  p er  gr o u p).   A  c c or di n gl y, 
s u bj e cts  1- 1 2 0   will  b e r a n d o  mi z e d i nt o  P art   A  a n d s u bj e cts  1 2 1- 4 2 0   will  b e r a n d o  mi z e d i nt o  P art   B. 
S u bj e cts r a n d o  mi z e d i n  P art   A   will  n ot  b e  eli gi bl e t o  p arti ci p at e i n  P art   B.  
F oll o  wi n g  c o  m pl eti o n  of  P art   A, t h e s p o ns or   will  c o n d u ct  a  pl a n n e d,  u n bli n d e d  a n al ysis  of t h e  P art  A 
GI t ol er a bilit y  a n d s af et y  d at a.  P art   B   will  b e  o n g oi n g  d uri n g t h e  a n al ysis  of t h e  P art   A  d at a.   D at a fr o  m 
P art   A  c a n  b e  us e d t o   m o dif y t h e  P art   B   GI t ol er a bilit y  e n d p oi nt(s).   A  p o ol e d  a n al ysis  of  P arts   A  a n d   B 
will  n ot  b e  c  o n d u ct e d. 
All st u d y  visits i n  P arts   A  a n d   B   will  b e  c o  m pl et e d  o n  a n  o ut p ati e nt  b asis.  T h e s cr e e ni n g  p eri o d is  u p t o 
4   w e e ks ( 2 8  d a ys ) i n cl u di n g  a  1-w e e k l e a d  -i n  p eri o d ( pri or t o r a n d o  mi z ati o n)  d uri n g   w hi c h s u bj e cts 
will  c o  m pl et e t  w o s elf  -a d  mi nist er e d   GI s y  m pt o  m s c al es  d ail y  usi n g  e -di ari es.  
I n  P art   A  a n d  P art   B, s u bj e cts   m e eti n g t h e  eli gi bilit y  crit eri a   will  b e r a n d o  mi z e d i n  a  1: 1 r ati o t o  o n e  of 
t  w o  bli n d e d tr e at  m e nt  gr o u ps  as f oll o  ws: 
•  
Gr o u p  1:   A L  K S  8 7 0 0  4 6 2   m g   BI  D (  wit h  1-  w e e k titr ati o n)   


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  4  of  6 7 
•  
Gr o u p  2:   D  M F  2 4 0   m g   BI  D (  wit h  1  -w e e k titr ati o n)  . 
I n  e a c h  p art,  b ot h   A L  K S  8 7 0 0  a n d   D  M F   will  b e  a d  mi nist er e d  or all y   BI  D  as  bli n d e d st u d y  dr u g;  eit h er 
A L  K S  8 7 0 0  4 6 2   m g   BI  D  or   D  M F  2 4 0   m g   BI  D   wit h  a n i niti al  1-  w e e k  d os e titr ati o n  p eri o d.   N o  d os e 
r e d u cti o ns   will  b e  p er  mitt e d  d uri n g t h e st u d y. If  a s u bj e ct  d o es  n ot t ol er at e t h e st u d y  dr u g  d uri n g t h e 
i niti al  1-  w e e k  d os e titr ati o n  p eri o d  or  aft er t h e  d os e titr ati o n  p eri o d, t h e s u bj e ct   will  b e  dis c o nti n u e d 
fr o  m t h e st u d y.  
S u bj e cts   will  b e i nstr u ct e d t o t a k e st u d y  dr u g   wit h  or   wit h o u t f o o d. H o  w e v er s u bj e cts   will  b e i nstr u ct e d 
t o  a v oi d t a ki n g st u d y  dr u g   wit h  a  hi g h-f at,  hi g h-c al ori e   m e al.  
T h e st u d y  d ur ati o n f or  e a c h  p art is  a p pr o xi  m at el y  1 1  w e e ks,   w hi c h i n cl u d es  u p t o   4  w e e ks f or 
s cr e e ni n g (i n cl u di n g  a  1-w e e k l e a d  -i n  p eri o d),  a  5-w e e k   d o u bl e- bli n d tr e at  m e nt  p eri o d (  wit h  1- w e e k 
titr ati o n),  a n d  a  2-  w e e k f oll o  w- u p  p eri o d (f or s u bj e cts  n ot  c o nti n ui n g i nt o t h e   A L  K 8 7 0 0-  A 3 0 1 l o n g-
t er  m s af et y st u d y).   D uri n g t h e  5-w e e k tr e at  m e nt  p eri o d (  Visits  3  - 8), s u bj e cts   will r et ur n t o t h e  cli ni c f or 
w e e kl y s c h e d ul e d  visits f or  ass ess  m e nts  of s af et y, t ol er a bilit y, 
 
,  a n d  cli ni c al st at us.   A n y s u bj e ct   w h o  pr e  m at ur el y  dis c o nti n u es fr o  m t h e 
st u d y   will r et ur n t o t h e  cli ni c f or  a n  E T  visit (  Visit 8)  a n d  a f oll o  w- u p  visit (  Visit  9).  
S u bj e cts  c o  m pl eti n g t h e  e ntir e  5   w e e ks  of  d o u bl e- bli n d tr e at  m e nt i n  eit h er  P art   A  or  P art   B  of t h e st u d y 
will  b e  eli gi bl e t o  e nr oll i n  a l o n g  -t er  m,  o p e n-l a b el s af et y st u d y ( St u d y A L  K 8 7 0 0-  A 3 0 1  )  a n d r e c ei v e 
A L  K S  8 7 0 0 f or  u p t o  9 6   w e e ks.  S u bj e cts  n ot  e nr olli n g i n t h e l o n g-  t er  m s af et y st u d y   will r et ur n t o t h e 
cli ni c  2   w e e ks f oll o  wi n g   Visit  8 f or  a f oll o  w- u p  visit (  Visit  9).  
N u  m b e r  of  S u bj e cts  Pl a n n e d   ( P a rt   A  a n d  P a rt   B):   A p pr o xi  m at el y  4 2 0 s u bj e cts r a n d o  mi z e d ( 1 2 0 i n 
P art   A  a n d  3 0 0 i n  P art   B). 
M ai n   C rit e ri a f o r I n cl usi o n   ( P a rt   A  a n d  P a rt   B): M al e  a n d f e  m al e s u bj e cts  b et  w e e n  a g es  1 8  a n d 
6 5  y e ars  (i n cl usi v e)   wit h  a  c o nfir  m e d  di a g n osis  of   R  R  M S  a c c or di n g t o t h e r e vis e d M c  D o n al d  crit eri a 
(P ol  m a n,   R ei n g ol d  et  al.  2 0 1 1 ) ar e  eli gi bl e f or t h e st u d y . S u bj e cts   m ust  b e  n e ur ol o gi c all y st a bl e   wit h 
n o  e vi d e n c e  of r el a ps e   wit hi n  3 0  d a ys  pri or t o r a n d o  mi z ati o n.  All s u bj e cts   m ust  a gr e e t o  us e 
c o ntr a c e pti o n   w hil e  p arti ci p ati n g i n t h e st u d y  a n d f or  3 0  d a ys  aft er t h eir l ast  d os e  of st u d y  dr u g  u nl ess 
s ur gi c all y st eril e  or  p ost -m e n o p a us al.   
I n v esti g ati o n al  P r o d u ct,   D os a g e,   D u r ati o n  a n d   M o d e  of   A d  mi nist r ati o n  ( P a rt   A  a n d  P a rt   B): 
A L  K S  8 7 0 0  c a ps ul es ( 2 3 1   m g)    c o nsist  of  d el a y e d-r el e as e (  D  R) ( e nt eri c-c o at e d)   mi nit a bl ets  c o nt ai n e d 
wit hi n  a  h y dr o x y pr o p yl   m et h yl c ell ul os e (  H P  M  C)  c a ps ul e f or  or al   a d  mi nistr ati o n . 
T h e  d os es  of   A L  K S  8 7 0 0 t o  b e  us e d i n t his st u d y  ar e  2 3 1   m g  BI  D   ( a d  mi nist er e d  as  o n e  2 3 1   m g  c a ps ul e 
a n d  o n e  pl a c e b o  c a ps ul e  BI  D f or   t h e first   w e e k)  a n d  4 6 2   m g BI  D   ( a d  mi nist er e d  as t  w o  2 3 1   m g 
c a ps ul es  BI  D   f or t h e  n e xt f o ur w e e ks  ).  S u bj e cts   will  b e i nstr u ct e d t o t a k e  b ot h  c a ps ul es si  m ult a n e o usl y 
f or  b ot h   m or ni n g  a n d  e v e ni n g  d os es. S u bj e cts   will  b e i nstr u ct e d t o  t a k e st u d y  dr u g wit h  or   wit h o ut 
f o o d.   H o  w e v er s u bj e cts   will  b e i nstr u ct e d t o  a v oi d t a ki n g st u d y  dr u g   wit h  a  hi g h-f at,  hi g h-c al ori e   m e al.  
R ef e r e n c e   T h e r a p y,   D os a g e,   D u r ati o n  a n d   M o d e  of   A  d  mi nist r ati o n  ( P a rt   A  a n d  P a rt   B): 
C o  m  m er ci all y  a v ail a bl e   D  M F ( T e cfi d  er a ® ;   m a n uf a ct ur e d  b y   Bi o g e n I n c.  of   C a  m bri d g e,   M  A)   will  b e 
a d  mi nist er e d  as  eit h er  o n e  1 2 0   m g  c a ps ul e  or  o n e  2 4 0   m g  c a ps ul e f or  or al  a d  mi nistr ati o n.  T h e   D  M F 
c a ps ul e   will  b e  o v er - e n c a ps ul at e d t o  cr e at e  bli n d e d st u d y  dr u g.  T h e  pl a c e b o   m at c h e d t o t h e A L  K S 
8 7 0 0  a n d  D  M F  dr u g  pr o d u ct  c o nsists  of  pl a c e b o   mi nit a bl ets  c o nt ai n e d   wit hi n t h e s a  m e   H P  M  C  c a ps ul e 
us e d f or  o v er - e n c a ps ul ati o n  of   D  M F  dr u g  pr o d u ct f or  or al  a d  mi nistr ati o n. Pl a c e b o   will  b e  us e d   wit hi n 
t h e tr e at  m e nt  p eri o d t o   m ai nt ai n t h e  bli n d. 
T h e  d os es  of   D  M F t o  b e  us e d i n t his st u d y  ar e  1 2 0   m g   BI  D   ( a d  mi nist er e d  as  o n e  1 2 0   m g  c a ps ul e  a n d 
o n e  pl a c e b o  c a ps ul e  BI  D f or   t h e first w e e k  )  a n d  2 4 0   m g BI  D   (a d  mi nist er e d   as  o n e  2 4 0   m g  c a ps ul e  a n d 
o n e  pl a c e b o  c a ps ul e  BI  D f or   t h e  n e xt f o ur   w e e ks). S u bj e cts   will  b e i nstr u ct e d  t o t a k e st u d y  dr u g   wit h  or 
wit h o ut f o o d.  S u bj e cts   will  b e i nstr u ct e d t o t a k e  b ot h  c a ps ul es si  m ult a n e o usl y f or  b ot h   m or ni n g  a n d 
e v e ni n g  d os es. 








 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  8  of  6 7 
3.    
T  A  B  L  E   O F   C  O  N  T  E  N  T S   
1.  
TI T L E  P  A  G E  ................................................................................................................ 1 
C  O  N T  A  C T I  N F  O  R  M  A TI  O  N   .......................................................................................................... 2 
2.  
S  Y  N  O P SI S  ................................................................................................................... 3 
3.  
T  A  B L E   O F   C  O  N T E  N T S  ............................................................................................. 8 
4.  
LI S T   O F   A  B  B  R E  VI  A TI  O  N S..................................................................................... 1 2  
5.  
I  N T  R  O  D  U  C TI  O  N ...................................................................................................... 1 4 
5. 1.  
Dis e as e   O v er vi e  w   ....................................................................................................... 1 4 
5. 2.  
Cli ni c al  St u di es   ........................................................................................................... 1 5 
5. 3.  
N o n cli ni c al  St u di es   ..................................................................................................... 1 6 
5. 4.  
D os e  S el e cti o n   ............................................................................................................ 1 7 
5. 5.  
St u d y   R ati o n al e  ........................................................................................................... 1 7 
6.  
O  BJ E  C TI  V E S   ............................................................................................................. 1 9 
7.  
S E L E  C TI  O  N   A  N  D   WI T  H  D  R  A  W  A L   O F  S  U  BJ E  C T S  .............................................. 2 0 
7. 1.  
S u bj e ct  I n cl usi o n   Crit eri a ........................................................................................... 2 0 
7. 2.  
S u bj e ct  E x cl usi o n   Crit eri a  .......................................................................................... 2 0 
7. 3.  
S u bj e ct   Wit h dr a  w al  .................................................................................................... 2 2 
7. 4.  
R e pl a c e  m e nt  of  S u bj e cts   ............................................................................................. 2 3 
8.  
S T  U  D  Y   D E SI  G  N  ....................................................................................................... 2 4 
8. 1.  
O v er all  St u d y   D esi g n  a n d  Pl a n   ................................................................................... 2 4 
8. 2.  
S c h e d ul e  of   Visits  a n d   Ass ess  m e nts ........................................................................... 2 5  
8. 3.  
St u d y  Pr o c e d ur es   D es cri pti o ns ................................................................................... 2 9  
8. 3. 1.  
I nf or  m e d   C o ns e nt ....................................................................................................... 2 9 
8. 3. 2.  
C o nfir  m ati o n  of   Willi n g n ess t o   C o nti n u e i n t h e  St u d y .............................................. 2 9  
8. 3. 3.  
Eli gi bilit y   R e vi e  w  ....................................................................................................... 2 9 
 
2 9  
8. 3. 4.  
D e  m o gr a p hi cs  a n d   M e di c al   Hist or y ........................................................................... 2 9  
8. 3. 5.  
C o n c o  mit a nt   M e di c ati o n   R e vi e  w ............................................................................... 2 9  
8. 3. 6.  
Vit al  Si g ns   .................................................................................................................. 3 0 
8. 3. 7.  
P h ysi c al  E x a  mi n ati o n  ................................................................................................. 3 0 
8. 3. 8.  
B o d y   H ei g ht  a n d   W ei g ht ............................................................................................ 3 0  
8. 3. 9.  
1 2- L e a d  El e ctr o c ar di o gr a  m  ........................................................................................ 3 0 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  9  of  6 7 
8. 3. 1 0.  
Str u ct ur e d I nt er vi e  ws  a n d   Q u esti o n n air es .................................................................. 3 0  
8. 3. 1 0. 1.  
GI  S y  m pt o  m  S c al es   .................................................................................................... 3 0 
 
3 1  
 
3 2  
 
3 2  
 
3 2  
8. 3. 1 0. 6.  
C ol u  m bi a  S ui ci d e  S e v erit y   R ati n g  S c al e (  C  -S S  R S)  ................................................... 3 2 
8. 3. 1 1.  
Br ai n   M a g n eti c   R es o n a n c e I  m a gi n g   ........................................................................... 3 2 
8. 3. 1 2.  
L a b or at or y   Ass ess  m e nts  ............................................................................................. 3 3 
8. 3. 1 2. 1.  
H e  m at ol o g y,   Bi o c h e  mistr y,  a n d   Uri n al ysis   ................................................................ 3 3 
8. 3. 1 2. 2.  
Pr e g n a n c y  T esti n g  ...................................................................................................... 3 3 
8. 3. 1 2. 3.  
S er ol o g y  T esti n g ......................................................................................................... 3 4  
8. 3. 1 3.  
R a n d o  mi z ati o n ............................................................................................................ 3 4  
8. 3. 1 4.  
Dr u g   Dis p e ns ati o n  a n d   R e c o n cili ati o n ....................................................................... 3 4  
8. 3. 1 5.  
A d v ers e  E v e nt   M o nit ori n g ......................................................................................... 3 4  
8. 4.  
St u d y   R e q uir e  m e nts  a n d   R estri cti o ns ......................................................................... 3 4  
8. 4. 1.  
C o ntr a c e pti o n  a n d  Pr e g n a n c y ..................................................................................... 3 5  
8. 4. 2.  
Pr o hi bit e d   M e di c ati o ns ............................................................................................... 3 6  
9.  
T  R E  A T  M E  N T   O F  S  U  BJ E  C T S .................................................................................. 3 8  
9. 1.  
St u d y   Dr u g   D os e  a n d   A d  mi nistr ati o n  ......................................................................... 3 8 
9. 2.  
Tr e at  m e nt   A d h er e n c e  .................................................................................................. 3 8 
9. 3.  
R a n d o  mi z ati o n/  M et h o d  of   Assi g ni n g  S u bj e cts t o  Tr e at  m e nt ..................................... 3 8  
9. 4.  
Bli n di n g ...................................................................................................................... 3 9  
9. 5.  
R es c u e   ......................................................................................................................... 3 9 
 
3 9  
 
4 0  
1 0.  
S T  U  D  Y   D  R  U  G   M  A T E  RI  A L S  A  N  D   M  A  N  A  G E  M E  N T   ........................................... 4 1 
1 0. 1.  
St u d y   Dr u g  .................................................................................................................. 4 1 
1 0. 1. 1.  
A L  K S  8 7 0 0 ................................................................................................................. 4 1  
1 0. 1. 2.  
Di  m et h yl  F u  m ar at e   ..................................................................................................... 4 1 
1 0. 1. 3.  
Pl a c e b o  ........................................................................................................................ 4 1 
1 0. 2.  
P a c k a gi n g  a n d  L a b eli n g  .............................................................................................. 4 1 
1 0. 3.  
St or a g e  ........................................................................................................................ 4 1 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 0  of  6 7 
1 0. 4.  
A c c o u nt a bilit y ............................................................................................................. 4 1  
1 0. 5.  
H a n dli n g  a n d   Dis p os al ................................................................................................ 4 2  
1 1.  
A S S E S S  M E  N T   O F  S  A F E T  Y   A  N  D  T  O L E  R  A  BI LI T  Y   ............................................. 4 3 
1 1. 1.  
D efi niti o n  of   A d v ers e  E v e nt ....................................................................................... 4 3  
1 1. 2.  
D efi niti o n  of  S eri o us   A d v ers e  E v e nt .......................................................................... 4 3  
1 1. 3.  
R el ati o ns hi p t o  St u d y   Dr u g ........................................................................................ 4 4  
1 1. 4.  
M o nit ori n g  a n d   R e c or di n g  of   A d v ers e  E v e nts ........................................................... 4 6  
1 1. 5.  
R e p orti n g  of  S eri o us   A d v ers e  E v e nts ......................................................................... 4 6  
1 2.  
A S S E S S  M  E  N T   O F  E F FI  C  A  C  Y  ................................................................................ 4 7 
 
4 8  
1 4.  
S T  A TI S TI  C S  .............................................................................................................. 4 9 
1 4. 1.  
S a  m pl e  Si z e   C o nsi d er ati o ns ....................................................................................... 4 9  
1 4. 2.  
G e n er al  St atist  i c al   M et h o d ol o g y ................................................................................ 4 9 
1 4. 2. 1.  
St u d y  P o p ul ati o n(s) .................................................................................................... 4 9  
1 4. 3.  
E n d p oi nts .................................................................................................................... 4 9  
1 4. 3. 1.  
Pri  m ar y  E n d p oi nt ........................................................................................................ 4 9  
1 4. 3. 2.  
S e c o n d ar y  E n d p oi nts .................................................................................................. 5 0  
1 4. 4.  
D e  m o gr a p hi cs  a n d   B a  s eli n e   C h ar a ct eristi cs  ............................................................... 5 0 
1 4. 5.  
S af et y   A n al ys es ( P art   A  a n d  P art   B) ........................................................................... 5 0 
1 4. 6.  
GI  T ol er a bilit y   A n al ys es ( P art   A  a n d  P art   B)   ............................................................. 5 1 
1 4. 7.  
E x pl or at or y  Effi c a c y   A n al ys es ( P art   A  a n d  P art   B)  ................................................... 5 1 
 
5 1  
1 5.  
DI R E  C T   A  C  C E S S  T  O  S  O  U  R  C E   D  A T  A/  D  O  C  U  M E  N T S  ......................................... 5 3 
1 5. 1.  
St u d y   M o nit ori n g ........................................................................................................ 5 3  
1 5. 2.  
A u dits  a n d I ns p e cti o ns ................................................................................................ 5 3  
1 5. 3.  
I nstit uti o n al   R e vi ew   B o ar d/I n d e p e n d e nt  Et hi cs   C o  m  mitt e e ...................................... 5 3  
1 6.  
Q  U  A LI T  Y   C  O  N T  R  O L   A  N  D   Q  U  A LI T  Y   A S S  U  R  A  N  C E   ......................................... 5 4 
1 6. 1.  
C as e   R e p ort  F or  ms   ..................................................................................................... 5 4 
1 6. 2.  
C o nfi d e nti alit y  of   D at a ............................................................................................... 5 4  
1 7.  
E T  HI C  A L   C  O  N SI  D E  R  A TI  O  N S ................................................................................ 5 5 
1 7. 1.  
Et hi cs   R e vi e  w  ............................................................................................................. 5 5 
1 7. 2.  
Et hi c al   C o n d u ct  of t h e  St u d y ...................................................................................... 5 5  
1 7. 3.  
Writt e n I nf or  m e d   C o ns e nt .......................................................................................... 5 5  


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 1  of  6 7 
1 7. 4.  
C o nfir  m ati o n  of   Willi n g n ess t o   C o nti n u e i n t h e  St u d y .............................................. 5 6  
1 8.  
D  A T  A   H  A  N  D LI  N  G   A  N  D   R E  C  O  R  D  K E E PI  N  G   ....................................................... 5 7 
1 8. 1.  
D at a   C a pt ur e   ............................................................................................................... 5 7 
1 8. 2.  
I ns p e cti o n  of   R e c or ds ................................................................................................. 5 7 
1 8. 3.  
R et e nti o n  of   R e c or ds .................................................................................................. 5 7  
1 8. 4.  
Us e  of I nf or  m ati o n  a n d  P u bli c ati o n  P oli c y ................................................................ 5 8  
1 9.  
R E F E  R E  N  C E S   ........................................................................................................... 5 9 
A P P E  N  DI  X   A.  I  N  DI  VI  D  U  A L   G  A S T  R  OI  N TE S TI  N  A L  S  Y  M P T  O  M   A  N  D  I  M P  A  C T 
S  C  A L E (I  GI SI S)  ......................................................................................................... 6 1 
A P P E  N  DI  X   B.  G L  O  B  A L   G  A S T  R  OI  N T E S TI  N  A L  S  Y  M P T  O  M   A  N  D I  M P  A  C T 
S  C  A L E (  G  GI SI S)  ....................................................................................................... 6 5 
 
 
LI S  T   O F   T  A  B  L  E S   
T a bl e   1: 
St u d y   C o nt a ct I nf or  m ati o n ........................................................................................... 2  
T a bl e   2: 
S c h e d ul e  of   Ass ess  m e nts ( P art   A  a n d  P art   B)  ............................................................ 2 6 
T a bl e   3: 
Cli ni c al  L a b or at or y   Ass ess  m e nts   ............................................................................... 3 3 
T a bl e   4: 
St u d y   Dr u g   D osi n g  S c h e d ul e ( P art   A  a n d  P art   B) ...................................................... 3 8  
T a bl e   5: 
A d v ers e  E v e nt   C a us alit y   G ui d eli n es   .......................................................................... 4 5 
 
LI S  T   O F  F  I  G  U  R  E S 
Fi g ur e   1: 
St u d y   D esi g n  S c h e  m ati c ( P art   A  a n d  P art   B)  ............................................................. 2 5 
 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 2  of  6 7 
4.    
LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N  S  
T h e f oll o  wi n g  a b br e vi ati o ns  ar e  us e d i n t his st u d y  pr ot o c ol. 
A b b r e vi ati o n  o r   T e  r  m    
E x pl a n ati o n  o r   D efi niti o n   
A E   
A  d v ers e  E v e nt  
A L T   
A  l a ni n e   A  mi n otr a nsf er as e 
A  N  C  O  V  A   
A  n al ysis  of  C o v ari a n c e 
A S T   
A  s p art at e A  mi n otr a nsf er as e 
A  U  C   
A  r e a U n d er   t h e C o n c e ntr ati o n  -Ti  m e  c ur v e  
A  U  C l ast 
A  r e a u n d er t h e  pl as  m a  c o n c e ntr ati o n  v ers us ti  m e  c ur v e  c al c ul at e d  usi n g 
t h e tr a p e z oi d al   m et h o d fr o  m ti  m e  z er o t o t h e l ast  o bs er v e d 
c o n c e ntr ati o n  a b o v e t h e l o  w er li  mit  of  q u a ntifi c ati o n 
BI  D   
T wi c e   D ail y   
CI   
C o nfi d e n c e   I nt er v al 
C m a x   
M a xi  m u  m  o bs er v e d  c o n c e ntr ati o n 
C  R  O   
C  o ntr a ct r es e ar c h  or g a ni z ati o n  
C S  A   
Cli ni c al  St u d y   A gr e e  m e nt   
C- S S  R S  
C  ol u  m bi a  S ui ci d e  S e v erit y   R ati n g  S c al e  
C  V  %   
P er c e nt  c o effi ci e nt  of  v ari ati o n  
D  M F   
Di  m et h yl   F u  m ar at e  ( T e cfi d er a® ) 
D  M T   
D  is e as e-  M o dif yi n g  T h er a pi es 
D  R   
D  el a y e d   R el e as e  
IE  C  
I n d e p e n d e nt Et hi cs   C o  m  mitt e e  
E  C  G  
E l e ctr o c ar di o gr a  m 
e  C  R F  
E l e ctr o ni c   C as e   R e p ort  For  m  
e  G F  R  
E sti  m at e d  gl o  m er ul ar filtr ati o n r at e 
E  D S S  
E x p a n d e d   Dis a bilit y  St at us  S c al e  
E T  
E arl y  F er  mi n ati o n  
E  Q - 5  Q- 5 L 
E ur o  Q o L   Gr o u p  h e alt h  o ut c o  m e   m e as ur e 
F  A S  
F ull  A n al ysis  S et   
F S  
F u n cti o n al  S yst e  m  
G  C P   
G o o d   Cli ni c al  Pr a cti c e   
GI   
G  astr oi n t esti n al 
G  GI SI S   
Gl o b al   GI  S y  m pt o  m  a n d I  m p a ct  S c al e 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 3  of  6 7 
A b b r e vi ati o n  o r   T e  r  m    
E x pl a n ati o n  o r   D efi niti o n   
HI  V   
H u  m a n I  m  m u n o d efi ci e n c y   Vir us 
H P  M  C   
H y dr o x y pr o p yl   M et h yl c ell ul os e   
I  C F 
I nf or  m e d   C o ns e nt  F or  m 
I  C  H 
I nt er n ati o n al   C o nf er e n c e  o n   H ar  m o nis ati o n of  T e c h ni c al   R e q uir e  m e nts 
f or   R e gistr ati o n  of  P h ar  m a c e uti c als f or   H u  m a n   Us e 
I  GI SI S 
I n di vi d u al   GI  S y  m pt o  m  a n d I  m p a ct  S c al e 
I  R  B 
I nstit uti o n al   R e vi e  w   B o ar d 
M e d  D  R  A   
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es   
M  M F   
M o n o  m et h yl   F u  m ar at e  
M  RI   
M  a g n eti c  R es o n a n c e I  m a gi n g 
M S   
M  ulti pl e  S cl er osis  
P  K  
P h ar  m a c o ki n eti c  
P  M L  
P r ogr essi v e  M ultif o c al  L e u k o e n c e p h al o p at h y 
Q T c  B   
Q T i nt er v al  c orr e ct e d  usi n g   B a z ett’s f or  m ul a   
Q T c F   
Q T i nt er v al  c orr e ct e d  usi n g  Fri d eri ci a’s f or  m ul a   
R  D  C  - 6 5 6 7 
M et a b olit e  of   A L  K S  8 7 0 0 
R  R  M S   
R el a psi n g-  R e  mitti n g   M ulti pl e  S cl er osis   
S  A E  
S eri o us   A d v ers e  E v e nt  
S  A P  
S t atisti c al A n al ysis  Pl a n   
S  D  
St a n d ar d  D e vi ati o n   
 
 
 
 
T E  A E  
T r e at  m e nt-E  m er g e nt   A d v ers e  E v e nt  
T S  H  
T h yr oi d- Sti  m ul ati n g   H or  m o n e 
U L  N   
U  p p er li  mit  of  N or  m al   
W  H  O   
W orl d   H e alt h   Or g a ni z ati o n 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 4  of  6 7 
5.    
I  N  T  R  O  D  U  CTI  O  N 
5. 1.    
Dis e as e   O v e r vi e  w   
M ulti pl e s cl er osis (  M S) is  a  pr o gr essi v e  n e ur ol o gi c al  dis e as e   m ar k e d  b y  d e  m y eli n ati o n  a n d 
a x o n al  d estr u cti o n t h at  c urr e ntl y  aff e cts  a p pr o xi  m at el y  2. 5   milli o n  p e o pl e   w orl d  wi d e   wit h  5 t o 
1 0  n e  w  c as es  p er  1 0 0, 0 0 0  p e o pl e  e a c h  y e ar ( R o p p er  2 0 1 2  ); (Tr e  ml ett,  Z h a o  et  al.  2 0 1 0 ). 
R  el a psi n g -r e  mitti n g   M S (  R  R  M S) is t h e   m ost  c o  m  m o n f or  m  of   M S   wit h  8 0 t o  9 0  %  of  all   M S 
p ati e nts i niti all y  pr es e nti n g   wit h  a n   R  R  M S  dis e as e  c o urs e.   Wit h o ut  tr e at  m e nt,  p ati e nts  c a n 
e x p eri e n c e fr e q u e nt r el a ps es,  a si g nifi c a nt  d e cr e as e i n  q u alit y  of lif e ,  a n d  c a n  d e v el o p t h e   m or e 
s e v er e t y p e, s e c o n d ar y-pr o gr essi v e   M S, l e a di n g t o s e v er e  p h ysi c al  dis a bilit y.  
Alt h o u g h   M S r e  m ai ns  a n i n c ur a bl e,  c hr o ni c  dis e as e, r e c e  nt t h er a p e uti c  a d v a n c e  m e nts  h a v e l e d t o 
si g nifi c a nt i  m pr o v e  m e nt i n t h e   m a n a g e  m e nt  of t h e  dis e as e.   Dis e as e -  m o dif yi n g t h er a pi es (  D  M Ts) 
ar e   wi d el y  us e d f or t h e tr e at  m e nt  of r el a psi n g f or  ms  of   M S ( M ulti pl e  S cl er osis   C o aliti o n  2 0 1 5  ) 
a n d  h a v e  b e e n  d e  m o nstr at e d t o  d el a y  dis e as e  pr o gr essi o n,  pr e v e n t  dis a bilit y,  a n d i  m pr o v e  q u alit y 
of lif e.   Of t h e  a p pr o v e d   D  M Ts,  T e cfi d er a ®  ( di  m et h yl f u  m ar at e [  D  M F] (Bi o g e n    2 0 1 5)  is  a first-
li n e  or al t h er a p y t h at  h as  b e c o  m e  o n e  of t h e   m ost  c o  m  m o nl y  pr es cri b e d  a g e nts f or t h e tr e at  m e nt 
of r el a psi n g f or  ms  of   M S  d u e t o its r o b ust  effi c a c y  a n d  o v er all f a v or a bl e s af et y  pr ofil e ( D u b e y, 
Ki es ei er  et  al.  2 0 1 5  ). 
D  M F is  a f u  m ari c  a ci d  est er s alt t h at  u n d er g o es r a pi d  pr es yst e  mi c  h y dr ol ysis t o its  a cti v e 
m et a b olit e,   m o n o  m et h yl f u  m ar at e (  M  M F)   (P hilli ps  a n d  F o x  2 0 1 3 ) (W er d e n b er g, J os hi  et  al.   
2 0 0 3 ) .   W hil e   D  M F  a n d,  b y  e xtr a p ol ati o n, its   m et a b olit e,   M  M F,  h a v e  d e  m o nstr at e d r o b ust 
effi c a c y  a n d  a f a v or a bl e s af et y  pr ofil e i n  P h as e  3  pi v ot al  cli ni c al tri als (  D E FI  N E  a n d   C  O  N FI R  M;  
(G ol d,   K a p p os  et  al.  2 0 1 2  ); (P hilli ps  a n d  F o x  2 0 1 3 ), g astr oi nt esti n al (  GI)  a d v ers e  e v e nts (  A Es) 
w er e  c o  m  m o nl y r e p ort e d  a n d t h e l e a di n g  c a us e  of st u d y  dr u g  dis c o nti n u ati o n  d u e t o   A Es (  C e nt er 
f or   Dr u g  E v al u ati o n  a n d   R es e ar c h  2 0 1 3).  T h e  gr e at est i n ci d e n c e  of   GI   A Es  o c c urr e d i n t h e first 
m o nt  h  of tr e at  m e nt  (C e nt er f or   Dr u g  E v al u ati o n  a n d   R es e ar c h  2 0 1 3  );(P hilli ps,  S el  m aj  et  al. 
2 0 1 5 ). I n  a d diti o n,   m or e t h a n  a t hir d  of  p ati e nts  e x p eri e n ci n g   GI s y  m pt o  ms  d uri n g t h e first t hr e e 
m o nt hs  of tr e at  m e nt  h a d t h eir   D  M F  d os a g e i nt err u pt e d, r e d u c e d,  or  dis c o nti n u e d,   w hi c h  c o ul d 
l e a d t o l ess t h a n  o pti  m al l e v els  of   M  M F (P hilli ps,  S el  m aj  et  al.  2 0 1 5 ). 
I n  a d diti o n t o t h e  P h as e  3 st u di es, s u bs e q u e nt   D  M F  cli ni c al tri als  utili zi n g   GI s y  m pt o  m 
q u esti o n n air es ( F o x,   V as q u e z  et  al.  2 0 1 4 ); (O'  G or  m a n,   R uss ell  et  al.  2 0 1 5  ); (T or n at or e,  Li  et  al. 
2 0 1 4 ) as   w ell  as  "r e al  w orl d " r e gistr y st u di es   (C h a v es,   G a n g ul y  et  al.  2 0 1 5  ) h a v e r e p ort e d  e v e n 
hi g h er r at es  of   GI  e v e nts  a n d  dis c o nti n u ati o ns  d u e t o   GI  e v e nts,  p er h a ps r efl e cti v e  of  a   m or e 
a c c ur at e  a n d  c o  m pl et e  pi ct ur e  of  p ati e nt  e x p eri e n c e.   Cli ni c al  d at a i n di c at e t h at   GI  e v e nts 
r e pr es e nt  a n i  m p ort a nt iss u e f or  p ati e nts t a ki n g   D  M F,  a n d t h er e is  a  n e e d t o i  m pr o v e  o n GI  -
r el at e d t ol er a bilit y t o miti g at e   r el at e d  n e g ati v e  c o ns e q u e n c es, i n cl u di n g iss u es   wit h tr e at  m e nt 
a d h er e n c e  a n d  dis c o nti n u ati o n. 
Al k er  m es is  d e v el o pi n g   A L  K S  8 7 0 0  as  a n  or al tr e  at  m e nt f or r el a psi n g f or  ms  of   M S .   A L  K S  8 7 0 0 
is  a n  a  mi n o  et h yl  est er  of   M  M F t h at  u n d er g o es  h y dr ol ysis t hr o u g h  est er as es t o  pr o d u c e   M  M F. 
M  M F is t h e  a cti v e   m et a b olit e i n t  h e  a p pr o v e d  dr u g,  T e cfi d er a ®  ( di  m et h yl f u  m ar at e [  D  M F]), 
w hi c h is  eff e cti v e i n tr e ati n g r el a psi n g f or  ms  of   M S.    T h e   A L  K S  8 7 0 0  dr u g  pr o d u ct is  a t  wi c e 
d ail y  (  BI  D),  d el a y e d r el e as e (  D  R)  or al  d os a g e f or  m  k n o  w n  as   A L  K S  8 7 0 0   D  R (f or  c o n v e ni e n c e, 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 5  of  6 7 
h o  w e v er, it   will  b e r ef err e d t o  as  “  A L  K S  8 7 0 0 ” i n t his  d o c u  m e nt).   B as e d  o n  n o n cli ni c al st u di es 
t o  d at e,   A L  K S  8 7 0 0 is r a pi dl y  c o n v ert e d t o   M  M F i n  vi v o,  a n d s yst e  mi c   A L  K S  8 7 0 0  e x p os ur e 
h as  n ot  b e e n  o bs er v e d.  T h e   A L  K S  8 7 0 0  dr u g  pr o d u ct  yi el ds   M  M F  e x p os ur e  c o  m p ar a bl e t o 
D  M F,  a n d   is e x p e ct e d t o  pr o vi d e  effi c a c y  c o  m p ar a bl e t o   D  M F   wit h  p ot e nti all y i  m pr o v e d  GI 
t ol er a bilit y. 
5. 2.    
Cli ni c al  St u di es   
F o ur  P h as e  1  st udi es t o  e v al u at e t h e s af et y, t ol er a bilit y,  a n d  p h ar  m a c o ki n eti cs ( P  K ) of   A L  K S 
8 7 0 0 i n  h e alt h y  a d ults ( St u d y  A L  K 8 7 0 0- 0 0 1  ,   A L  K 8 7 0 0-  A 1 0 2,   A L  K 8 7 0 0-  A 1 0 3,  a n d 
A L  K 8 7 0 0-  A 1 0 4  )  h a v e  b e e n  c o  m pl et e d. F o ur  P h as e  1 st u d i es (A L  K 8 7 0 0-  A 1 0  5 ,   A L  K 8 7 0 0-  A 1 0 6, 
A L  K 8 7 0 0-  A 1 0 7  ,  a n d A L  K 8 7 0 0-  A 1 0 9  )  h av e  b e e n  cli ni c all y  c o  m pl et e d  a n d t h e  d at a  a n al ys es  ar e 
o n g oi n g. 
T h e  g e n er al  p h ar  m a c o ki n eti c  c h ar a ct eristi cs  h a v e  b e e n  e v al u at e d i n t h e   a b o v e  m e nti o n e d 
c o  m pl et e d  P h as e  1 st u di es.   A L  K S  8 7 0 0  u n d er g o es r a pi d  pr es yst e  mi c  h y dr ol ysis t o   M  M F   wit h  a 
d os e  pr o p orti o n at e i n cr e as e i n   M  M F  e x p os ur e  o v er t h e   A L  K S  8 7 0 0  d os e r a n g e  t est e d ( 4 9 t o 
9 8 0   m g;   A L  K 8 7 0 0- 0 0 1). 
A d  mi nistr ati o n  of   A L  K S  8 7 0 0  4 2 0   m g   wit h  a  hi g h-  f at, hi g h -c al ori e   m e al   d el a y e d  a bs or pti o n  of 
M  M F  , r es ulti n g i n  a si g nifi c a nt  d e cr e as e i n m a xi  m u  m  o bs er v e d  c o n c e ntr ati o n (  C m a x ) ( 4 4  %)  a n d  a 
m o d est r e d u cti o n i n   A  U  C l ast ( 1 1  %) (  A L  K 8 7 0 0-  A 1 0 2). Mi ni  m al  a c c u  m ul ati o n  of   M  M F   w as 
o bs er v e d i n  pl as  m a f oll o  wi n g r e p e at e d  a d  mi nistr ati o n  of  2 1 0 t o  6 3 0   m g  BI  D   f or 5  d a ys  
(  A L  K 8 7 0 0-  A 1 0 2). I n  a d diti o n,   R  D  C- 6 5 6 7  h as  b e e n i d entifi e d  as  a   m aj or  h u  m a n   m et a b olit e  of 
A L  K S  8 7 0 0 t h at is  pri  m aril y  eli  mi n at e d i n  uri n e (  A L  K 8 7 0 0-  A 1 0 5). 
T h e r el ati v e  bi o a v ail a bilit y  of   A L  K S  8 7 0 0  4 6 2  m g   c o  m p ar e d   wit h    D  M F  2 4 0   m g w as i niti all y 
e v al u at e d i n  a  f ast e d  c o n diti o n (  A L  K 8 7 0 0-  A 1 0 3) as   w ell  as  i n t h e  pr es e n c e  of  a  hi g h-f at, 
hi g h -c al ori e   m e al (  A L  K 8 7 0 0 -  A 1 0 4).   A L  K S  8 7 0 0  4 6 2   m g r es ult e d i n si  mil ar   M  M F  e x p os ur e t o 
D  M F  2 4 0   m g  u n d er f ast e d  c o n diti o ns  a n d   m et t h e  P  K  crit eri a f or  bi o e q ui v al e n c e t o   D  M F  b as e d 
o n   C m a x   a n d   A  U  C (  A L  K 8 7 0 0-  A 1 0 3).  A L  K S    8 7 0 0  4 6 2 m g r es u  lt e d is si  mil ar   M  M F  e x p os ur e t o 
D  M F  2 4 0   m g   wit h  a  hi g h  -f at, hi g h -c al ori e   m e al  a n d   m et t h e  P  K  crit eri a f or  bi o e q ui v al e n c e t o 
D  M F f or   A  U  C,  b ut   C m a x    w as  2 6  % l o  w er f or   A L  K S  8 7 0 0  as  c o  m p ar e d t o   D  M F 
(  A L  K 8 7 0 0-  A 1 0 4). 
Gi v e n t h e r e d u cti o n i n   C m a x  wit h  a  hi g h  -f at,  hig h - c al ori e   m e al,  a n  a d diti o n al st u d y   w as  c o n d u ct e d 
e v al u ati n g   m e al  c o  m p ositi o ns   wit h l o  w er f at  a n d  c al ori c  c o nt e nt. I n t his st u d y (  A L  K 8 7 0 0-  A 1 0 9), 
M  M F   A  U  C f or   A L  K S  8 7 0 0,   w h e n  a d  mi nist er e d   wit h   m e di u  m-f at,   m e di u  m-  c al ori e  a n d l o  w -f at, 
l o  w-c al ori e   m e als , w as  c  o  m p ar a bl e t o   D  M F  u n d er f ast e d  c o n diti o ns.  A d  mi nistr ati o n  of 
A L  K S    8 7 0 0   wit h   m e di u  m-f at,   m e di u  m-c al ori e  a n d l o  w -f at, l o  w-c al ori e   m e als r es ult e d i n 
r e d u cti o ns i n   Cm a x t h at   w er e l ess t h a n t h at  o bs er v e d f or   D  M F   w h e n  a d  mi nist er e d   wit h  a  hi g h-f at, 
hi g h -c al ori e   m e al (  A L  K 8 7 0 0-  A 1 0 9). T h er ef or e,   w h e n  c o- a d  mi nist er e d   wit h   m e di u  m -f at, 
m e di u  m- c al ori e  a n d l o  w-  f at, l o  w- c al ori e   m e als,   A L  K S  8 7 0 0 r es ult e d i n   M  M F  e x p os ur e   wit hi n 
t h e  a c c e pt e d t h er a p e uti c  e x p os ur e r a n g e f or   D  M F.   A c c or di n gl y,   A L  K S  8 7 0 0  c a n  b e  a d  mi nist er e d 
wit h  or   wit h o ut f o o d  b ut s h o ul d  b e  a v oi d e d   wit h  hi g h-  f at, hi g h -c al ori e   m e als  as  d es cri b e d i n 
S e cti o n  9. 1 . 
O v er all s af et y  a n al ys es fr o  m t h e  a b o v e  m e nti o n e d  c o  m pl et e d   P h as e  1  cli ni c al st u di es  h a v e 
d e  m o nstr at e d t h at   A L  K S  8 7 0 0  h as  b e e n  g e n er all y   w ell t ol er at e d  at  all  d os es t est e d  ( 4 9   m g t o 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 6  of  6 7 
9 8 0  m g)     wit h  n o r e p ort e d s eri o us  a d v ers e  e v e nts ( S  A Es)  a n d  n o  u n a nti ci p at e d  or  u nf or es e e n 
cli ni c al s af et y iss u es  aft er  si n gl e  or r e p e at  d osi n g i n  h e alt h y s u bj e cts.   All r e p ort e d  tr e at  m e nt 
e  m er g e nt  a d v ers e  e v e nts ( T E  A Es )  h a v e  b e e n   mil d  or   m o d er at e i n s e v erit y ( pr e d o  mi n a ntl y   mil d), 
a n d t h er e  h a v e  b e e n  n o r el e v a nt  diff e r e n c es i n t ol er a bilit y  b et  w e e n si n gl e  a n d r e p e at  d osi n g  at 
t h e s a  m e  d os e l e v els.  T h e   m ost  c o  m  m o nl y r e p ort e d  T E  A Es  h a v e  b e e n fl us hi n g f oll o  w e d  b y 
GI  - T E  A Es   w hi c h  h a v e  b ot h  o c c urr e d i n  a  d os e- d e p e n d e nt   m a n n er.   GI- T E  A Es  h a v e  b e e n 
o bs er v e d   wit h   A L  K S  8 7 0 0  at  c o nsist e ntl y l o  w r at es t hr o u g h o ut t h e st u di es  at  d os e l e v els 
c o  m p ar a bl e (i n t er  ms  of   M  M F  e x p os ur e) t o t h e t h er a p e uti c   m ai nt e n a n c e  d os e  of   D  M F ( 2 4 0   m g). 
R es ults fr o  m  P h as e  1  cli ni c al i n v esti g ati o ns  a v ail a bl e t o  d at e  o n t h e  p h ar  m a c o ki n eti cs, s af et y, 
a n d t ol er a b ilit y  of   A L  K S  8 7 0 0  ar e s u  m  m ari z e d i n t h e I n v esti g at or’s   Br o c h ur e. 
5. 3.    
N o n cli ni c al  St u di es   
A  c o  m pr e h e nsi v e s eri es  of  n o n cli ni c al st u di es   w er e  c o n d u ct e d t o s u p p ort t h e  cli ni c al 
d e v el o p  m e nt  of   A L  K S  8 7 0 0  a n d  ar e  d es cri b e d i n   m or e  d et ail i n t h e  A L  K S  8 7 0 0   I n v esti g ator’s 
Br o c h ur e  . 
R es ults fr o  m  g e n eti c t o xi cit y  ass a ys s h o  w e d t h at   A L  K S  8 7 0 0   w as  n o n-  m ut a g e ni c i n  b a ct eri a 
i n  vitr o a n d   w as  ass o ci at e d   wit h  c hr o  m os o  m al  a b err ati o ns  i n  vitr o i n  h u  m a n  p eri p h er al  bl o o d 
l y  m p h o c yt es  b ut  n ot i n  vi v o i n r ats.   A L  K S  8 7 0 0  h a d li  mit e d  c a p a cit y t o i n hi bit  h E  R  G ( h u  m a n 
et h er - à-g o -g o -r el at e d  g e n e) p ot assi u  m  c h a n n el  a cti vit y i n  a  h u  m a n  c ell li n e  (i e, I C5 0  > 3 0 0  µ  M). 
I n hi biti o n  of  h E  R  G  c urr e nt  h as  b e e n  ass o ci at e d   wit h i n cr e as e d  d ur ati o n  of t h e  c ar di a c  a cti o n 
p ot e nti al  a n d  pr ol o n g ati o n  of  t h e Q T   i nt er v al. 
G e n er al t o xi c ol o g y fi n di n gs   w er e  g e n er all y si  mil ar t o t h os e  d es cri b e d f or   D  M F  a n d  c o nsist e d  of 
t ar g et  or g a n  eff e cts i n  ki d n e y (t u b ul ar  d e g e n er ati o n/ n e cr osis   wit h r e g e n er ati o n, t u b ul ar 
h y p ertr o p h y,  a n d i nt erstiti al fi br osis i n r ats,   mi c e,  a n d/ or  m o n k e ys),  g astr oi nt esti n al tr a ct 
(  m u c os al  h y p er pl asi a  of t h e  n o n gl a n d ul ar st o  m a c h  a n d  d u o d e n u  m  of r ats  a n d/ or   mi c e),  b o n e 
( p h ys e al  d ys pl asi a  of  pr o xi  m al  a n d  dist al f e  m ur  a n d  pr o xi  m al ti bi a i n   m o n k e ys),  h e art 
(i nfl a  m  m ati o n/ n e cr osis i n r ats),  a n d t est es (  mi ni  m al  d e g e n er ati o n i n   mi c e). 
A L  K S  8 7 0 0   w as  e v al u at e d f or  d e v el o p  m e nt al  a n d r e pr o d u cti v e t o xi cit y i n r ats  a n d r a b bits. I n 
f ertilit y st u di es i n   m al e  a n d f e  m al e r ats,  n o  n ot a bl e f ertilit y  or  e  m br y o ni c  d e v el o p  m e nt al fi n di n gs 
o c c urr e d . I n  e  m br y o-f et al  d e v el o p  m e nt st u di es i n r ats  a n d r a b bits,  n ot e  w ort h y fi n di n gs  of f et al 
v ert e br al   m alf or  m ati o ns   w er e  o bs er v e d i n r a b bits  b ut  n ot i n r ats. 
T h e s af et y  e v al u ati o n  of   A L  K S  8 7 0 0  a n d its   m et a b olit es (i e,   M  M F,   R  D  C- 6 5 6 7,  a n d   R  D  C- 8 4 3 9) 
w as  a d e q u at e  as s yst e  mi c  e x p os ur es  of t h e  s e  a n al yt es i n  n o n cli ni c al st u di es   w er e si  mil ar t o  or 
e x c e e d e d t h os e i n  h u  m a ns  at t h e  P h as e  3  cli ni c al  d os e  of  9 2 4   m g/ d a y ( 4 6 2   m g   BI  D)  of 
A L  K S    8 7 0 0.  F or t h e   m aj or  h u  m a n   m et a b olit es   M  M F  a n d   R  D  C- 6 5 6 7, t h e  e x p os ur es  ass o ci at e d 
wit h  a d v ers e fi n di n gs i n  n o n cli n  i c al s af et y st u di es  ar e  d et ail e d i n t h e   A L  K S  8 7 0 0 I n v esti g at or’s 
Br o c h ur e  . 
D at a  g e n er at e d t hr o u g h  a d diti o n al  n o n cli ni c al st u di es   will  c o nti n u e t o  b e  e v al u at e d  as t h e y 
b e c o  m e  a v ail a bl e, i n cl u di n g  a n y  p ot e nti al i nfl u e n c e  o n t h e ris k -b e n efit  pr ofil e  of   A L  K S  8 7 0 0. 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 7  of  6 7 
5. 4.    
D os e  S el e cti o n   
T h e s el e ct e d  d os e l e v el  of   A L  K S  8 7 0 0 ( 4 6 2   m g) is s u p p ort e d  b y  cli ni c al s af et y, t ol er a bilit y,  a n d 
P  K  d at a fr o  m  pri or  cli ni c al st u di es ( St u d y  A L  K 8 7 0 0- 0 0 1  ,   A L  K 8 7 0 0-  A 1 0 2, A L  K 8 7 0 0-  A 1 0 3  , 
a n d  A L  K 8 7 0 0-  A 1 0 4  ). 
T h e  d os es  of   A L  K S  8 7 0 0 t o  b e  us e d f o r i niti al  d os e titr ati o n ( 2 3 1   m g)  a n d f or tr e at  m e nt 
m ai nt e n a n c e ( 4 6 2   m g) i n t his st u d y  ar e   wit hi n t h e r a n g e  of  d os es  e v al u at e d i n  a  c o  m pl et e d si n gl e 
as c e n di n g  d os e st u d y ( St u d y  A L  K 8 7 0 0- 0 0 1  )  a n d i n  a  c o  m pl et e d r e p e at  d os e  cli ni c al st u d y 
( St u d y A L  K 8 7 0 0-  A 1 0 2  ).  S af et y  d at a fr o  m  b ot h st u di es ( St u d y   A L  K 8 7 0 0- 0 0 1  a n d 
A L  K 8 7 0 0-  A 1 0 2) i n di c at e t h at  d os es  of  2 1 0   m g,  4 2 0   m g  a n d  6 3 0   m g ( br a c k eti n g t h e  d os es t o  b e 
us e d i n t his st u d y),  a d  mi nist er e d  eit h er  as  a si n gl e  d os e  or t  wi c e  d ail y f or fi v e  d a ys i n  h e alt h y 
s u bj e cts   w ere  g e n er all y   w ell t ol er at e d   wit h  n o r el e v a nt  diff er e n c es i n s af et y  or t ol er a bilit y 
b et  w e e n si n gl e  or r e p e at  d osi n g  at  e a c h  d os e l e v el. I n  a d diti o n, fr o  m  St u d y   A L  K 8 7 0 0-  A 1 0 2, i t 
w as  d e  m o nstr at e d t h at t h e i n ci d e n c e  of fl us hi n g   wit h   A L  K S  8 7 0 0   w as l o  w er i n t h e f e d  c o n diti o n 
( 3 7. 5  %  of s u bj e cts)  c o  m p ar e d t o t h e f ast e d  c o n diti o n ( 5 0. 0  %  of s u bj e cts). 
T h e  a p pr o pri at e n ess  of  a   m ai nt e n a n c e  4 6 2   m g  d os e  of   A L  K S  8 7 0 0   w as  c o nfir  m e d  b y t  w o 
r el ati v e  bi o a v ail a bilit y st u di es ( St u d y A L  K 8 7 0 0-  A 1 0 3    a n d A L  K 8 7 0 0-  A 1 0 4  )   w h er e  P  K r es ults 
s h o  w t h at   A L  K S  8 7 0 0  4 6 2   m g r es ults i n  c o  m p ar a bl e   M  M F  e x p os ur e t o   D  M F  2 4 0   m g  u n d er 
f ast e d  c o n diti o ns,  as   w ell  as i n t h e  pr es e n c e  of  a  hi g h-f at, hi g h -c al ori e   m e al.   M  M F  e x p os ur e 
f oll o  wi n g  a d  mi nistr ati o n  of   A L  K S  8 7 0 0  pr o vi d es  c o  m p ar a bl e  e x p os ur e t o   D  M F i n t he f ast e d 
c o n diti o n ( St u d y  A L  K 8 7 0 0-  A 1 0 3  ) a n d  m et t h e  P  K  crit eri a f or  bi o e q ui v al e n c e t o   D  M F f or   A  U  C 
a n d   C m a x .   W hil e t ot al s yst e  mi c  e x p os ur e t o   M  M F   w as  c o  m p ar a bl e  b et  w e e n   A L  K S  8 7 0 0  a n d 
D  M F i n t h e  pr es e n c e  of  a  hi g h-  f at, hi g h -c al ori e   m e al,   C m a x    w as  2 6  % l o  w er (A L  K 8 7 0 0-  A 1 0 4  ). I n 
a s u bs e q u e nt st u d y ( A L  K 8 7 0 0-  A 1 0 9  ), it   w as f o u n d t h at   m e di u  m-f at,   m e di u  m-c al ori e  a n d l o  w -
f at, l o  w-c al ori e   m e als r es ult e d i n r e d u cti o ns i n   C m a x  t h at   w er e  n o  gr e at er t h a n t h at  o bs er v e d   wit h 
D  M F   w h e n  c o  -a d  mi nist er e d   wit h  a  hi g h -f at, hi g h -c al o ri e   m e al. T h er ef or e,  A L  K S  8 7 0 0  c a n  b e 
t a k e n   wit h  or   wit h o ut f o o d. H o  w e v er  , s u bj e cts   will  b e i nstr u ct e d t o  a v oi d t a ki n g st u d y  dr u g   wit h 
a  hi g h -f at,  hi g h-c al ori e   m e al.  A d  mi nistr ati o n   wit h f o o d   m a y r e d u c e t h e i n ci d e n c e  of fl us hi n g ( as 
o bs er v e d i n  St u d y  A L  K 8 7 0  0-  A 1 0 2 ). 
T h e  d os e l e v els  of   D  M F i n t his st u d y ( 1 2 0   m g   BI  D  d uri n g i niti al  d os e titr ati o n f oll o  w e d  b y 
2 4 0   m g   BI  D  as   m ai nt e n a n c e  d os e)  ar e  c o nsist e nt   wit h t h e  a p pr o v e d  d os e  a d  mi nistr ati o n 
i nf or  m ati o n i n t h e  T e cfi d er a l a b el (Bi o g e n  2 0 1 5  ). A d diti o n all y, t h e  T e cfi d er a l a b el st at es t h at 
T e cfi d er a  c a n  b e t a k e n   wit h  or   wit h o ut f o o d  a n d t h at  a d  mi nistr ati o n   wit h f o o d   m a y   r e d u c e t h e 
i n ci d e n c e  of fl us hi n g (Bi o g e n  2 0 1 5  ). 
5. 5.    
St u d y   R ati o n al e  
C o  m pl et e d  P h as e  1  cli ni c al st u di es t o  d at e   wit h   A L  K S  8 7 0 0 i n  h e alt h y  v ol u nt e ers  h a v e i n di c at e d 
l o  w r at es  of   GI   A Es   wit h  a  p ot e nti all y f a v or a bl e   GI t ol er a bilit y  pr ofil e  c o  m p ar e d t o   D  M F.  T his 
P h as e  3 st u d y,  c o n d u ct e d i n t  w o  p arts (  A  a n d   B), is  d esi g n e d t o f urt h er  e v al u at e t h e   GI 
t ol er a bilit y  of   A L  KS  8 7 0 0 i n r el ati o n t o   D  M F i n  a  p ati e nt  p o p ul ati o n   wit h   R  R  M S  usi n g t  w o 
s u bj e ct-r at e d   GI s y  m pt o  m s c al es: t h e I n di vi d u al   GI  S y  m pt o  m  a n d I  m p a ct  S c al e [I  GI SI S]  a n d t h e 
Gl o b al   GI  S y  m pt o  m  a n d I  m p a ct  S c al e [  G  GI SI S].   
T h e st u d y   will  utili z e  a n  a d a pti v e  a p pr o a c h,   w h er e  d at a fr o  m  P art   A  c a n  b e  us e d t o   m o dif y t h e 
GI t ol er a bilit y  e n d p oi nt(s) i n  P art   B. ( T h e  c o nt e nt  of t h e t  w o   GI s y  m pt o  m s c al es t h e  ms el v es   will 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 8  of  6 7 
n ot  b e   m o difi e d  b et  w e e n  P art   A  a n d  P art   B.)   A c c or di n gl y,  P art   A   will s er v e  as  a n i niti al 
e x pl or at or y  e v al u ati o n  o f t h e t  w o   GI s y  m pt o  m s c al es (S e cti o n  8. 3. 1 0. 1 )  a n d  e n d p oi nts  d eri v e d 
fr o  m t h e s c al es   w hil e  P art   B   will s er v e  as  a  c o nfir  m at or y  e v al u ati o n  of t h e s c al es  a n d r el at e d 
e n d p oi nts  as i nf or  m e d fr o  m  P art   A. I n  a d diti o n,  t his t  w o- p art  d esi g n  all o  ws f or  u ni nt err u pt e d  a n d 
s e q u e nti al  e nr oll  m e nt  of  P art   A  a n d  P art   B  u n d er  o n e  pr ot o c ol   wit h  ass o ci at e d l o gisti c al 
effi ci e n ci es.  
B ot h  P arts   A  a n d   B  ar e i d e nti c al i n st u d y  d esi g n  a n d i n cl u d e  a  5-  w e e k,  d o u bl e-  bli n d tr e at  m e nt 
p eri o d   wit h t  w o  bli n d e d tr e at  m e nt  ar  ms (  A L  K S  8 7 0 0  a n d   D  M F).  E a c h  p art,  h o  w e v er,   will  b e 
a n al y z e d s e p ar at el y  a n d   will  n ot  b e  p o ol e d. 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  1 9  of  6 7 
6.    
O  B J  E  C  TI  V  E S 
T h e  o bj e cti v es  of t his st u d y  ar e t o: 
•    E v al u at e t h e  utilit y  of t  w o   GI s y  m pt o  m s c al es (I  GI SI S  a n d   G  GI SI S)  a n d  e n d p oi nts 
d eri v e d fr o  m t h e s c al es i n  ass essi n g   GI t ol er a bilit y i n  a d ult s u bj e cts   wit h   R  R  M S  aft er 
a d  mi nistr ati o n  of   A L  K S  8 7 0 0  or   D  M F i n  P art   A  
•    C o  m p ar e t h e   GI t ol er a bilit y  of   A L  K S  8 7 0 0  a n d   D  M F i n  a d ult s u bj e cts   wit h   R  R  M S 
usi n g t  w o   GI s y  m pt o  m s c al es (I  GI SI S  a n d   G  GI SI S) i n  P art   B   wit h  e n d p oi nts 
i nf or  m e d fr o  m  P art   A 
•    E v al u at e t h e s af et y  a n d t ol er a bilit y  of   A L  K S  8 7 0 0 i n  a d ult s u bj e cts   wit h   R  R  M S i n 
P arts   A  a n d   B  


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  2 0  of  6 7 
7.    
S  E  L  E  C  TI  O  N   A  N  D   WI  T  H  D  R A  W  A  L   O F  S  U  B J  E  C  T S   
7. 1.    
S u bj e ct I n cl usi o n   C rit e ri a  
1.    Is   willi n g  a n d  a bl e t o  pr o vi d e i nf or  m e d  c o ns e nt 
2.    C a p a bl e    of  u n d erst a n di n g  a n d  c o  m pl yi n g   wit h t h e  pr ot o c ol 
3.    M al e  a n d f e  m al e  a d ults  a g e d  1 8 t o  6 5  y e ars, i n cl usi v e,  at s cr e e ni n g (  Visit  1) 
4.    H as  a  c o nfir  m e d  di a g n osis  of   R  R  M S  a c c or di n g t o t h e r e vis e d  2 0 1 0   M c  D o n al d  crit eri a 
(P ol  m a n,   R ei n g ol d  et  al.  2 0 1 1 ) 
5.    B as eli n e  E x p a n d e d   Dis a bilit y  St at us  S c al e ( E  D S S) s c or e  of  0. 0  - 6. 0  at 
s cr e e ni n g (Visit    1)  a n d r a n d o  mi z ati o n (  Visit 3) 
6.    N e ur ol o gi c all y st a bl e   wit h  n o  e vi d e n c e  of r el a ps e   wit hi n  3  0  d a ys  pri or t o r a n d o  mi z ati o n 
(  Visit 3) 
7.    A gr e es t o  us e  a n  a c c e pt a bl e   m et h o d  of  c o ntr a c e pti o n f or t h e  d ur ati o n  of t h e st u d y  a n d f or 
3 0  d a ys  aft er  a n y st u d y  dr u g  a d  mi nistr ati o n  or is s ur gi c all y st eril e  or  p ost-  m e n o p a us al 
(s e e S e cti o n  8. 4. 1 ) 
7. 2.    
S u bj e ct  E x cl usi o n   C rit e ri a   
1.    H a v e  a n y fi n di n g(s) t h at i n t h e  vi e  w  of t h e I n v esti g at or  or t h e   M e di c al   M o nit or   w o ul d 
c o  m pr o  mis e t h e s af et y  of t h e s u bj e ct , aff e ct t h e s u bj e ct’s   a bilit y t o  a d h er e t o t h e  pr ot o c ol 
visit s c h e d ul e  or t o f ul fill  visit r e q uir e  m e nts, or  w o ul d   m a k e t h e s u bj e ct  u ns uit a bl e f or 
p arti ci p ati o n i n t h e st u d y (i n cl u di n g  o v er all  cli ni c al  ass ess  m e nt)  
2.    Di a g n osis  of  pri  m ar y  pr o gr essi v e, s e c o n d ar y  pr o gr essi v e,  or  pr o gr essi v e r el a psi n g   M S  as 
d efi n e d  b y  L u bli n  a n d   R ei n g ol d ( L u bli n  a n d   R ei n g ol d  1 9 9 6 ) 
3.    Hist or y  of  cli ni c all y si g nifi c a nt  c ar di o v as c ul ar,  p ul  m o n ar y,  g astr oi nt esti n al   (i n cl u di n g 
i nfl a  m  m at or y  b o  w el  dis e as e,  p e pti c  ul c er  dis e as e  a n d irrit a bl e  b o  w el s y n dr o  m e), 
d er  m at ol o gi c,  ps y c hi atri c,  n e ur ol o gi c ( ot h er t h a n   M S),  e n d o cri n e, r e n al  a n d/ or  ot h er 
m aj or  dis e as e t h at   w o ul d  pr e cl u d e  p arti ci p ati o n i n  a  cli ni c al tri al   
4.    Hist or y  of   GI s ur g er y ( e x c e pt  a p p e n d e ct o  m y t h at  o c c urr e d   m or e t h a n  6   m o nt hs  pri or t o 
s cr e e ni n g;  ot h er  pri or s ur g eri es   m a y  b e  p er  mitt e d  b as e d  o n   M e di c al   M o nit or  a p pr o v al) 
5.    Hist or y  of  cli ni c all y si g nifi c a nt r e c urri n g  or  a cti v e  g astr oi nt esti n al s y  m pt o  ms   ( e g,  n a us e a, 
di arr h e a,  d ys p e psi a,  c o nsti p ati o n)   wit hi n  3   m o nt hs  of s cr e e ni n g 
6.    C hr o ni c  us e ( ≥ 7  d a ys)  of   m e di c al t h er a p y t o tr e at  a n y   GI s y  m pt o  ms   wit hi n  1   m o nt h  of 
s cr e e ni n g,  u nl ess  a n  e x c e pti o n is  gr a nt e d  b y t h e   M e di c al   M o nit or 
7.    H as  a  cli ni c all y si g nifi c a nt   m e di c al  c o n diti o n  or  o bs er v e d  a b n or  m alit y  at s cr e e ni n g 
( e g, cli ni c all y si g nifi c a nt  p h ysi c al  e x a  mi n ati o n fi n di n g,  vit al si g n r es ult,  E  C  G r es ult,  or 
l a b or at or y t est r es ult) 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  2 1  of  6 7 
8.    T  w o  or   m or e I n di vi d u al   GI  S y  m pt o  ms  a n d I  m p a ct  S c al e (I  GI SI S)   i n di vi d u al s y  m pt o  m 
i nt e nsit y s c or es  ≥ 3  d uri n g t h e  1- w e e k l e a d  -i n  e v al u ati o n  p eri o d  pri or t o r a n d o  mi z ati o n 
(  Visit 3) 
9.    C o  m pl et es  < 7 5  %  of t h e I  GI SI S  a n d/ or   G  GI SI S  e di ar y  e ntri es s c h e d ul e d t o  b e  c o  m pl et e d 
d uri n g t h e l e a d-i n  p eri o d  pri or t o r a n d o  mi z ati o n (  Visit  3)  u nl ess  a n  e x c e pti o n is  gr a nt e d  
b y t h e   M e di c al   M o nit or 
1 0.  Hist or y  of   m ali g n a n c y,  u nl ess  a n  e x c e pti o n is  gr a nt e d  b y t h e   M e di c al   M o nit or 
( e g, s u bj e cts   wit h  b as al  c ell  c ar ci n o  m a t h at  h as  b e e n  c o  m pl et el y  e x cis e d  pri or t o st u d y 
e ntr y   m a y  r e  m ai n  eli gi bl e) 
1 1.  Hist or y  of  a   m y o c ar di al i nf ar cti o n, i n cl u di n g  a sil e nt   m y o c ar di al i nf ar cti o n i d e ntifi e d  o n 
E  C  G,  or  u nst a bl e  a n gi n a  
1 2.  Hist or y  of  cli ni c all y si g nifi c a nt  dr u g  or  al c o h ol  a b us e   wit hi n t h e  p ast  y e ar   pri or t o 
s cr e e ni n g ( p er I n v esti g at or j u d g  m e nt) 
1 3.  P ositi v e s er ol o g y t est f or  h e p atitis   C  a nti b o d y,  h e p atitis   B s urf a c e  a nti g e n (  H  Bs  A g),  or 
h u  m a n i  m  m u n o d efi ci e n c y  vir us (  HI  V)  a n ti b o d y  at s cr e e ni n g (  Visit  1) 
1 4.  A  n y  of t h e f oll o  wi n g  a b n or  m al  bl o o d t ests  at s cr e e ni n g (  Visit  1):  
•    Al a ni n e  a  mi n otr a nsf er as e   (  A L T)  or  as p art at e a  mi n otr a nsf er as e  (  A S T)  ≥ 2 ti  m es t h e 
u p p er li  mit  of  n or  m al (  U L  N)  
•    T h yr oi d -sti  m ul ati n g  h or  m o n e ( T S  H) l e v el  hi g h er t h a n t h e  U L  N   b y  1 0  %  or   m or e  at 
s cr e e ni n g 
•    Esti  m at e d  gl o  m er ul ar filtr ati o n r at e ( e  G F  R)  ≤ 6 0   m L/  mi n/ 1. 7 3  m 2 ( usi n g t h e   C  K  D-E PI 
e q u ati o n; ( L e v e y,  St e v e ns  et  al.  2 0 0 9 ) 
•    L y  m p h o c yt e  c o u nt  < 0. 9  x  1 0 3/ μ L 
1 5.  A  n y  of t h e f oll o  wi n g  a b n or  m al  uri n e t ests  at s cr e e ni n g (  Visit  1):  
•    B et a  - 2   mi cr o gl o b uli n  > 0. 3  μ g/  m L 
•    Al b u  mi n t o  cr e ati ni n e r ati o  >  2 0 0  m g/ g   
1 6.  C  li ni c all y si g nifi c a nt  hist or y  of s ui ci d al i d e ati o n  or s ui ci d al  b e h a vi or i n t h e l ast 
1 2  m o nt hs  as  ass ess e d  b y t h e   C ol u  m bi a  S ui ci d e  S e v erit y   R ati n g  S c al e (  C  -S S  R S)  at 
s cr e e ni n g (  Visit  1) 
1 7.  Hist or y  of tr e at  m e nt   wit h  or  h as r e c ei v e d t h e f oll o  wi n g:   
•    F u  m a d er  m ® ,  T e cfi d er a, t ot al l y  m p h oi d irr a di ati o n,  cl a dri bi n e,  T-c ell  or 
T- c ell  r e c e pt or  v a c ci n ati o n, t ot al  b o d y irr a di ati o n  or t ot al l y  m p h oi d irr a di ati o n  at  a n y 
ti  m e 
•    St e  m  c ell tr a ns pl a nt ati o n  at  a n y ti  m e  
•    Mit o x a ntr o n e  or  ot h er i  m  m u n os u p pr ess a nt  a g e nts ( e g,  c y cl os p or  i n e, 
c y cl o p h os p h a  mi d e,   m et h otr e x at e,   m y c o p h e n ol at e)   wit hi n  2  y e ars  pri or t o 
r a n d o  mi z ati o n (  Visit  3) 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  2 2  of  6 7 
•    T erifl u n o  mi d e   wit hi n  2  y e ars  of   Visit  2 ,  u nl ess t h e s er u  m/ pl as  m a  c o n c e ntr ati o n  of 
t erifl u n o  mi d e is  < 0. 0 2 0   m c g/  m L ( < 2 0  n g/  m L) t o r a n d o  mi z ati o n (  Visit  3) ( a n 
a c c el er at e d  eli  mi n ati o n  pr o c e d ur e f or t erifl u n o  mi d e   wit h  c h ol est yr a  mi n e is  p er  mitt e d 
d uri n g s cr e e ni n g) 
•    N at ali z u  m a b   wit hi n  8   w e e ks  pri or t o   r a n d o  mi z ati o n (  Visit  3),  or  a n y  pri or  us e  of 
al e  mt u z u  m a b  
•    Fi n g oli  m o d   wit hi n  9 0  d a ys  pri or t o  r a n d o  mi z ati o n (  Visit  3) 
•    D  a cli z u  m a b   wit hi n  6  m o nt hs  pri or t o   Visit   3 
•    B-  c ell t ar g et e d t h er a pi es f or t h e tr e at  m e nt  of   M S ( e g,  o cr eli z u  m a b, rit u xi  m a b)   wit hi n 
1 2   m o nt hs  of s cr e e ni n g;  gr e at er t h a n  1 2   m o nt hs  of s cr e e ni n g is  p er  missi bl e   wit h 
e vi d e n c e t h at  t h e   C  D 1 9  c ells  h a v e r et ur n e d t o   wit hi n n or  m al r a n g e ( p er l o c al l a b 
r ef er e n c e r a n g e) 
•    Eli gi bilit y r el at e d t o  pri or tr e at  m e nt   wit h  a n i n v esti g ati o n al  dr u g   a n d/ or  a 
c o  m  m er ci all y  a v ail a bl e  dr u g  f or t h e tr e at  m e nt  of   M S  n ot list e d  a b o v e wit hi n t h e  p ast 
2 4   m o nt hs  will  b e  d et er  mi n e d  o n  a  c as e  -b y - cas e  b asis  b y  t h e   M e di c al   M o nit or 
•    St er oi ds,   wit h t h e  e x c e pti o n  of t o pi c al  or i n h al e d st er oi ds,  or I  V i  m  m u n o gl o b uli n 
wit hi n  3 0  d a ys  pri or t o r a n d o  mi z ati o n   (  Visit 3) 
1 8.  C urr e nt  or  pri or  p arti ci p ati o n i n  a  cli ni c al tri al   wit hi n  3   m o nt hs  of s cr e e ni n g (  Visit  1)   
1 9.  S u b j e ct is  pr e g n a nt  or  br e astf e e di n g  or  pl a ns t o  b e c o  m e  pr e g n a nt  or  b e gi n  br e astf e e di n g 
at  a n y  p oi nt  d uri n g t h e st u d y  a n d f or  3 0  d a ys  aft er  a n y st u d y  dr u g  a d  mi nistr ati o n 
2 0.  U n  willi n g n ess  or i n a bilit y t o  c o  m pl y   wit h t h e r e q uir e  m e nts  of t h e  pr ot o c ol, i n cl u di n g t h e 
pr es e n c e  of  a n y  c o n diti o n ( p h ysi c al,   m e nt al,  or s o ci al) t h at is li k el y t o  aff e ct t h e s u bj e ct’s 
a bilit y t o  c o  m pl y   wit h t h e  pr ot o c ol. 
2 1.  E  m pl o y e d  b y   Al k er  m es,  c o ntr a ct r es e ar c h  or g a ni z ati o n (  C  R  O)  or st u d y sit e ( p er  m a n e nt, 
t e  m p or ar y  c o ntr a ct   w or k er,  or  d esi g n e e r es p o nsi bl e f or t h e  c o n d u ct  of t h e st u d y)  or is 
i  m  m e di at e f a  mil y  of  a n   Al k er  m es,   C  R  O,  or st u d y sit e  e  m pl o y e e. I  m  m e di at e f a  mil y is 
d efi n e d  as  a s p o us e,  p ar e nt, si bli n g  or  c hil d,   w h et h er  bi ol o gi c al  or l e g all y  a d o pt e d. 
7. 3.    
S u bj e ct   Wit h d r a  w al  
I n  e a c h  P art,  a tr e at  m e nt  c o  m pl et er   will  b e  a s u bj e ct   w h o  c o  m pl et es t h e  5-  w e e k tr e at  m e nt  p eri o d. 
S u bj e cts  c o  m pl eti n g   Visit  8  will  b e  c at e g ori z e d  as  c o  m pl eti n g t h e st u d y.  A s u bj e ct   m a y  b e 
dis c o nti n u e d fr o  m t h e st u d y  at  a n y ti  m e if t h e s u bj e ct, I n v esti g at or,  or  S p o ns or  d et er  mi n es t h at it 
is  n ot i n t h e  b est i nt er est  of t h e s u bj e ct t o  c o nti n u e  p arti ci p ati o n.   R e as o ns f or  dis c o nti n u ati o n 
i n cl u d e: 
•    A d v ers e   e v e nt 
•    L a c k  of  e ffi c a c y 
•    L ost t o f oll o  w- u p 
•    Wit h dr a  w al   b y  s u bj e ct 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  2 3  of  6 7 
•    Pr ot o c ol  d e vi ati o n ( n o n- c o  m pli a n c e   wit h  St u d y   Dr u g  or  St u d y  Pr o c e d u r es) 
•    P h ysi ci a n  d e cisi o n  
•    Pr e g n a n c y  
•    St u d y  ter  mi n at e d  b y  s p o ns or 
•    Ot h er   
If  a s u bj e ct   wit h dr a  ws fr o  m t h e st u d y f or  a n y r e as o n ( e x c e pt f or   wit h dr a  w al  of  c o ns e nt),  a n y 
o n g oi n g   A Es   will  b e f oll o  w e d  u ntil r es ol uti o n,  u ntil  d e e  m e d st a bl e  b y t h e I n v esti g at or,  or  u nti l 
t h e s u bj e ct is  d e e  m e d  b y t h e I n v esti g at or t o  b e l ost t o f oll o  w- u p. If, i n t h e  o pi ni o n  of t h e 
I n v esti g at or, it is  n e c ess ar y t o   m o nit or  a s u bj e ct  b e y o n d t h e s af et y f oll o  w- u p  visit, t h e f oll o  w- u p 
p eri o d   m a y  b e  e xt e n d e d  as  n e c ess ar y. I n s u c h i nst a n c es, t h e  S p o ns or  a n d  In v esti g at or   will  a gr e e 
t o  a n  a c c e pt a bl e f oll o  w- u p s c h e d ul e. 
I n t h e  e v e nt t h at  a s u bj e ct  c h o os es t o   wit h dr a  w fr o  m t h e st u d y, t h e I n v esti g at or s h o ul d   m a k e  a 
r e as o n a bl e  eff ort t o  as c ert ai n t h e r e as o n(s) f or   wit h dr a  w al,   w hil e f ull y r es p e cti n g t h e s u bj e ct’s 
ri g hts.  S u bj e cts  dis c o nti n ui n g st u d y  dr u g  a n d   wit h dr a  wi n g fr o  m t h e st u d y ar e t o  b e  as k e d t o 
r et ur n t o t h e  cli ni c f or  a n E arl y  T er  mi n ati o n  (E T ) visit  (  Visit  8)  a n d a  f oll o  w- u p visit (  Visit  9 ). 
T h e  E T  visit  (  Visit  8) s h o ul d  b e s c h e d ul e d  as  cl os e  as  p ossi bl e t o t h e s u bj e ct’s l ast  d os e  a n d   will 
mi  mi c t h e  ass ess  m e nts s c h e d ul e d t o  b e  c o n d u ct e d  at   Visit   8 f or s u bj e cts   w h o  c o  m pl et e t h e 
5- w e e k tr e at  m e nt  p eri o d (s e e   T a bl e   2). If t h e s u bj e ct f ails  or r ef us es t o r et ur n t o t h e st u d y  c e nt er, 
a n  att e  m pt   m ust  b e   m a d e t o  c o nt a ct t h e s u bj e ct  b y t el e p h o n e i n  or d er t o  ass ess  as   m a n y s af et y 
a n d  effi c a c y  p ar a  m et ers  as  p ossi bl e.   All  d at a  c oll e ct e d  o v er t h e t el e p h o n e   m ust  b e  d o c u  m e nt e d 
a n d  k e pt i n t h e s u bj e ct’s r e c or d. 
T h e I n v esti g a t or   m ust   m ai nt ai n  a r e c or d  of  all s u bj e cts   w h o f ail t o  c o  m pl et e t h e st u d y.  T h e 
r e as o n f or st u d y  dis c o nti n u ati o n   will  b e  d o c u  m e nt e d  o n t h e  a p pr o pri at e  el e ctr o ni c  c as e r e p ort 
f or  m ( e  C  R F). If  a s u bj e ct is l ost t o f oll o  w- u p,  a r e as o n a bl e  att e  m pt t o  c o nt a ct t h e s u bj e ct   m ust  b e 
m a d e  a n d  d o c u  m e nt e d. 
7. 4.    
R e pl a c e  m e nt  of  S u bj e cts   
S u bj e cts   w h o   wit h dr a  w  aft er r e c ei vi n g t h e first  d os e  of st u d y  dr u g i n t his st u d y   will  n ot  b e 
r e pl a c e d. 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  2 4  of  6 7 
8.    
S  T  U  D  Y   D  E SI  G  N  
8. 1.    
O v e r all  St u d y   D esi g n  a n d  Pl a n   
T his is  a r a n d o  mi z e d,  d o u bl e- bli n d,   m ulti c e nt er  st u d y i n  a d ult s u bj e cts   wit h   R  R  M S  c o n d u ct e d i n 
t  w o  p arts ( P arts   A  a n d   B).  T h e st u d y  d esi g n is  a n  a d a pti v e  a p pr o a c h   w h er e  d at a fr o  m  P art   A  c a n 
b e  us e d t o   m o dif y t h e   GI t ol er a bilit y  e n d p oi nt(s) i n  P art   B. 
B ot h  P arts   A  a n d   B  ar e i d e nti c al i n st u d y  d esi g n  a n d   i n cl u d e  a  5-  w e e k,  d o u bl e-bli n d tr e at  m e nt 
p eri o d   wit h t  w o  bli n d e d tr e at  m e nt  ar  ms (  A L  K S  8 7 0 0  a n d   D  M F).  P art   A is  e x pl or at or y  a n d  P art 
B is  c o nfir  m at or y.  T h e first  1 2 0  eli gi bl e s u bj e cts   will  b e r a n d o  mi z e d t o  o n e  of t h e t  w o tr e at  m e nt 
gr o u ps i n  P art   A ( n = 6 0  p er  gr o u p).   O n c e t h e r a n d o  mi z ati o n f or  P art   A is  c o  m pl et e, t h e  n e xt  3 0 0 
eli gi bl e s u bj e cts   will  b e r a n d o  mi z e d i nt o  o n e  of t h e t  w o tr e at  m e nt  gr o u ps i n  P art   B ( n = 1 5 0  p er 
gr o u p).   A c c or di n gl y, s u bj e cts  1- 1 2 0   will  b e r a n d o  mi z e d i nt o  P art   A  a n d s u bj e cts  1 2 1-  4 2 0   wil l 
b e r a n d o  mi z e d i nt o  P art   B.  S u bj e cts r a n d o  mi z e d i n  P art   A   will  n ot  b e  eli gi bl e t o  p arti ci p at e i n 
P art   B.  
F oll o  wi n g  c o  m pl eti o n  of  P art   A, t h e s p o ns or   will  c o n d u ct  a  pl a n n e d,  u n bli n d e d  a n al ysis  of t h e 
P art  A   GI t ol er a bilit y  a n d s af et y  d at a.  P art   B   will  b e  o  n g oi n g  d uri n g t h e  a n al ysis  of t h e  P art   A 
d at a.   D at a fr o  m  P art   A  c a n  b e  us e d t o   m o dif y t h e  P art   B   GI t ol er a bilit y  e n d p oi nt(s).   A  p o ol e d 
a n al ysis  of  P arts   A  a n d   B   will  n ot  b e  c o n d u ct e d. 
All st u d y  visits i n  P arts   A  a n d   B   will  b e  c o  m pl et e d  o n  a n  o ut p ati e nt  b as  is.  T h e s cr e e ni n g  p eri o d 
is  u p t o  4   w e e ks i n cl u di n g  a  1-w e e k l e a d  -i n  p eri o d ( pri or t o r a n d o  mi z ati o n)  d uri n g   w hi c h 
s u bj e cts   will  c o  m pl et e t  w o s elf -a d  mi nist er e d   GI s y  m pt o  m s c al es  d ail y  usi n g  e -di ari es.  
I n  P art   A  a n d  P art   B, s u bj e cts   m e eti n g t h e  eli gi bilit y  crit eri a   will  b e r a n d o  mi z e d i n  a  1: 1 r ati o t o 
o n e  of t  w o  bli n d e d tr e at  m e nt  gr o u ps  as f oll o  ws: 
•    Gr o u p  1:   A L  K S  8 7 0 0  4 6 2   m g   BI  D (  wit h  1  -w e e k titr ati o n)   
•    Gr o u p  2:   D  M F  2 4 0   m g   BI  D (  wit h  1-  w e e k titr ati o n)   
I n  e a c h  p art,  b ot h   A L  K S  8 7 0 0  a n d   D  M F   will  b e  a d  mi nist er e d  or all y   BI  D  as  bli n d e d st u d y  dr u g; 
eit h er   A L  K S  8 7 0 0  4 6 2   m g   BI  D  or   D  M F  2 4 0   m g   BI  D   wit h  a n i niti al  1-  w e e k  d os e titr ati o n  p eri o d 
(T a bl e   4 ).  S u bj e cts   will  b e i nstr u ct e d t o t a k e st u d y  dr u g   wit h  or   wit h o ut f o o d. H o  w e v er s u bj  e cts 
will  b e i nstr u ct e d t o  a v oi d t a ki n g st u d y  dr u g   wit h  a  hi g h-f at,  hi g h-  c al ori e   m e al.  D osi n g is 
d es cri b e d i n  d et ail i n  S e cti o n  9. 1 . 
N o  d os e r e d u cti o ns   will  b e  p er  mitt e d  d uri n g t h e st u d y. If  a s u bj e ct  d o es  n ot t o  l er at e t h e st u d y 
dr u g  d uri n g t h e i niti al  1 -  w e e k  d os e titr ati o n  p eri o d  or  aft er t h e  d os e titr ati o n  p eri o d, t h e s u bj e ct 
will   b e  dis c o nti n u e d fr o  m t h e st u d y. 
T h e st u d y  d ur ati o n f or  e a c h  p art is  a p pr o xi  m at el y  1 1   w e e ks,   w hi c h i n cl u d es  u p t o  4   w e e ks f or 
s cr e e ni n g (i n cl u di n g  a  1- w e e k l e a d  -i n  p eri o d),  a  5-  w e e k  d o u bl e- bli n d tr e at  m e nt  p eri o d (  wit h 
1-  w e e k titr ati o n),  a n d  a  2- w e e k f oll o  w  - u p  p eri o d (f or s u bj e cts  n ot  c o nti n ui n g i nt o t h e 
A L  K 8 7 0 0-  A 3 0 1 l o n g-t er  m s af et y st u d y).   D uri n g t h e  5-  w e e k tr e at  m e nt  p eri o d (  Visits  3  - 8), 
s u bj e cts   will r et ur n t o t h e  cli ni c f or   w e e kl y s c h e d ul e d  visits f or  ass ess  m e nts  of s af et y, 
t ol er a bilit y, 
,  a n d  cli ni c al 




 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
 
C  O  N FI  D E  N TI  A L   
P a g e  2 6  of  6 7 
 
T a bl e  2:   
S c h e d ul e  of   Ass ess  m e nts  ( P a rt   A  a n d P a rt  B)   
 
S c r e e ni n g  
5- W e e k   R a n d o  mi z e d   T r e at  m e nt
1 
F oll o  w -
u p  
Visit   
1 2 
2 3   
3   
4   
5   
6   
7   
8 
(  E  T) 
9 
W e e k 
- 4   
- 1 
( ± 2 
d a ys ) 
1 
( ±3 
d a ys ) 
2 
( ±3 
d a ys ) 
3 
( ±3 
d a ys ) 
4 
( ±3 
d a ys ) 
5 
( ±3 
d a ys ) 
6 
( ±3 
d a ys ) 
8 
( ± 4  
d a ys ) 
I nf or  m e d   C o ns e nt 
X   
   
   
   
   
   
   
   
 
Eli gi bilit y   Crit eri a   R e vi e  w  
X   
   
X 4   
   
   
   
   
   
 
D e  m o gr a p hi cs   
X   
   
   
   
   
   
   
   
 
M e di c al   Hist or y   
X   
   
   
   
   
   
   
   
 
H ei g ht   
X   
   
   
   
   
   
   
   
 
W ei g ht   
X   
   
X 4   
   
   
   
   
X   
 
P h ysi c al  E x a  m 5  
X   
   
X 4   
   
   
   
   
X   
X 
C o n c o  mit a nt   M e di c ati o n   R e vi e  w   
X   
X   
X   
X   
X   
X   
X   
X   
X 
A d v ers e  E v e nt   M o nit ori n g   
X   
X   
X   
X   
X   
X   
X   
X   
X 
S er ol o g y  T esti n g 6 
X   
   
   
   
   
   
   
   
 
Pr e g n a n c y  T est 7 
X   
   
X 4 
   
   
   
   
   
 
Vit al  Si g ns 8 
X   
   
X 4   
X   
X   
X   
X   
X   
X 
St a n d ar d  1 2 -L e a d  E  C  G 9 
X   
   
X 4   
   
X   
   
   
X   
X 
Bi o c h e  m  istr y,   Uri n al ysis,   &   H e  m at ol o g y 
S a  m pl es 1 1 
X   
   
X 4   
   
X   
   
   
X   
X 








 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  3 0  of  6 7 
T h e  In v esti g at or   will r e c or d t h e f oll o  wi n g  d at a  o n  all   m e di c ati o ns  us e d  b y t h e s u bj e ct:  n a  m e, 
d os e, r e gi  m e n, r o ut e  of  a d  mi nistr ati o n, st art  a n d st o p  d at es,  a n d t h e i n di c ati o n f or  us e. 
8. 3. 6.    
Vit al  Si g ns   
Vit al si g ns (i e,  bl o o d  pr ess ur e,  p uls e, r es pir at or y r at e,  a n d t e  m p er at ur e)   will  b e  ass ess e d  at t h e 
ti  m e  p oi nts s p e cifi e d i n T a bl e   2.   Bl o o d  pr ess ur e,  p uls e,  a n d r es pir at or y r at e will  b e   m e as ur e d 
aft er t h e s u bj e ct  h as  b e e n r esti n g i n  a s e at e d  or s u pi n e  p ositi o n f or  at l e ast  5  mi n ut es.  C o nsist e nt 
m e as ur es  a n d  pr o c e d ur es s h o ul d  b e  us e d f or  all  ass ess  m e nts.  
As s p e cifi e d i n   T a bl e   2,  o n t h e first  d a y  of  d osi n g ( at r a n d o  mi z ati o n, Visit  3)  ,  vit al si g ns  ar e t o  b e 
m e as ur e d  pr e d os e.   
8. 3. 7.    
P h ysi c al   E x a  mi n ati o n 
A  p h ysi c al  e x a  mi n ati o n   will  b e  p erf or  m e d  at t h e ti  m e  p oi nt(s) s p e cifi e d i n   T a bl e   2. A f ull 
p h ysi c al  e x a  m   will  b e  c o n d u ct e d  at s cr e e ni n g  (  Visit  1)  a n d  bri ef, s y  m pt o  m-dir e ct e d  p h ysi c al 
e x a  m i n ati o ns will  b e  c o n d u ct e d  at  all  ot h er ti  m e  p oi nts.     D uri n g  visits   w h er e  bri ef, s y  m pt o  m-
dir e ct e d  p h ysi c al  e x a  mi n ati o ns  ar e s c h e d ul e d, if  a s u bj e ct  d o es  n ot r e p ort  a n y s y  m pt o  ms,  vi t al 
si g ns at   mi ni  m u  m  will  b e   m e as ur e d.   
8. 3. 8.    
B o d y   H ei g ht  a n d   W ei g ht 
M e as ur e  m e nt  of  b o d y  h ei g ht  a n d   w ei g ht   will  b e  p erf or  m e d  at t h e ti  m e  p oi nts s p e cifi e d i n 
T a bl e   2. 
8. 3. 9.    
1 2- L e a d   El e ct r o c a r di o g r a  m   
A  1 2  -l e a d  el e ctr o c ar di o gr a  m ( EC  G)   will  b e  c o n d u ct e d  at t h e ti  m e  p oi nts s p e cifi e d i n   T a bl e   2. 
E  C  Gs   will  b e  c oll e ct e d  pr e d os e  o n   Visit  3  a n d  at  a n y ti  m e  at  all  ot h er s c h e d ul e d  visits.   All 
s c h e d ul e d  E  C  Gs   m ust  b e  p erf or  m e d  aft er t h e s u bj e ct  h as r est e d  q ui etl y f or  at l e ast  5  mi n ut es i n   a 
s u pi n e  p ositi o n. 
E  C  Gs   will  b e  c o n d u ct e d  usi n g  c ali br at e d  e q ui p  m e nt  a n d  ass ess e d  b y  a  q u alifi e d  cli ni ci a n.   E  C  Gs 
will  b e  e v al u at e d  at t h e sit es  a n d  b y  a  c e ntr al r e a d er.   
8. 3. 1 0.    
St r u ct u r e d I nt e r vi e  ws  a n d   Q u esti o n n ai r es  
8. 3. 1 0. 1.    GI  S y  m pt o  m  S c al es   
T h e  GI s y  m pt o  m s c al es (  I n di vi d u al   GI  S y  m pt o  m  a n d I  m p a ct  S c al e [I  GI SI S]  a n d   Gl o b al   GI 
S y  m pt o  m  a n d I  m p a ct  S c al e [ G  GI SI S  ])   will  b e  c o  m pl et e d  b y s u bj e cts  usi n g  e-di ari es. 
A p pr o xi  m at el y   o n e  w e e k  pri or t o r a n d o  mi z ati o n (  W e e k   - 1),  eli gi bl e s u bj e cts   will r et ur n t o t h e 
sit e (  Visit  2) t o b e  tr ai ne d  o n t h e  c o  m pl et i o n of  t h e GI s y  m pt o  m   s c al es usi n g  e- di ari es  (s e e 
T a bl e   2). S u bj e cts  will  c o  m pl et e  b ot h   s c al es usi n g  e- di ari es   d ail y f or  7  d a ys  pri or t o 
r a n d o  mi z ati o n (  Visit 3)  t o f a cilit at e f a  mili arit y   wit h t h e s c al es  as   w ell  as t o  e v al u at e f or 
e x cl usi o n ar y   GI s y  m pt o  m at ol o g y (s e e  S e cti o n  7. 2 ,  E x cl usi o n   Crit eri o n # 8 ). 
F oll o  wi n g r a n d o  mi z ati o n  (  Visit  3), s u bj e cts   will  c o  m pl et e t h e I  GI SI S t  wi c e -d ail y  (s h o ul d  b e 
c o  m pl et e d  wit hi n   9  h o urs  aft er t a ki n g  e a c h  d os e  of st u d y  dr u g )  a n d t h e   G  GI SI S 
o n c e- d ail y  (e a c h    m or ni n g  pri or t o t a ki n g t h e   m or ni n g  d os e  of st u d y  dr u g; s e e T a bl e   2). 






 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  3 3  of  6 7 
8. 3. 1 2.    
L a b o r at o r y   Ass ess  m e nts 
8. 3. 1 2. 1.    H e  m at ol o g y,   Bi o c h e  mist r y,  a n d   U ri n al ysis 
Bl o o d  a n d  uri n e s a  m pl es f or l a b or at or y  ass ess  m e nts   will  b e  c oll e ct e d  at t h e ti  m e  p oi nts s p e cifi e d 
i n T a bl e   2.  S p e cifi c  h e  m at ol o g y,  bi o c h e  mistr y,  a n d  uri n al ysis  ass ess  m e nts  ar e list e d i n T a bl e   3. 
S a  m pl es   will  b e  c oll e ct e d i n  a c c or d a n c e   wit h t h e sit e’s  us u al  pr o c e d ur es  a n d  a n al y z e d  b y  a 
c e ntr al l a b or at or y.  
T a bl e  3:     
Cli ni c al   L a b o r at o r y   Ass ess  m e nts 
H e  m at ol o g y 
Bi o c h e  mist r y   
U r  i n al ysis 
H e  m at o crit   
H e  m o gl o bi n   
R e d  bl o o d  c ell  c o u nt   
T ot al  a n d  diff er e nti al ( a bs ol ut e) 
w hit e  bl o o d  c ell  c o u nt   
Pl at el ets  
S o di u  m  
P ot assi u  m  
C hl ori d e   
Bi c ar b o n at e   
Tri gl y c eri d es  
Gl u c os e   
T S  H 1 
C al ci u  m   
M a g n e si u  m   
P h os p h at e  
Uri c   A ci d   
Cr e ati ni n e   
T ot al  pr ot ei n  
Bl o o d  ur  e a  nitr o g e n (  B  U  N)  
Al b u  mi n   
T ot al  bilir u bi n  
A L T   
A S T   
L a cti c  d e h y dr o g e n a s e ( L  D  H)  
Al k ali n e  p h os p h at as e (  A L  K  -P)  
Cr e ati n e  p h o s p h o ki n as e (  C P  K)   
Li pi d  pr ofil e:  bl o o d  c h ol est er ol, 
hi g h -d e nsit y li p o pr ot ei n, l o  w -d e nsit y 
li p o pr ot ei n,  a n d tri gl y c eri d es 
C ol or   
p  H  
S p e cifi c  gr a vit y  
K et o n es   
Pr ot ei n  
Gl u c os e   
Bilir u bi n   
Nitrit e   
Ur o bili n o g e n   
O c c ult  bl o o d   
Mi cr os c o pi c  e x a  mi n ati o n  of 
s e di  m e nt o nl y if  uri n al ysis  di psti c k 
r es ults  ar e  a b n or  m al  
Uri n e  al b u  mi n   
Uri n e  b et a  - 2-mi cr o gl o b uli n   
Uri n e  cr e ati ni n e   
1  T o  b e  ass ess e d  at s cr e e ni n g  (  Visit 1)  o nl y . 
8. 3. 1 2. 2.    P r e g n a n c y   T esti n g  
As s p e cifi e d i n   T a bl e   2, a s er u  m  pr e g n a n c y t est   will  b e  p erf or  m e d f or  all   w o  m e n  r e g ar dl ess  of 
c hil d  b e ari n g  p ot e nti al  at s cr e e ni n g (  Visit  1); r es ults   m ust  b e  n e g ati v e f or t h e s u bj e ct t o  b e 
eli gi bl e f or t h e st u d y.   A  uri n e  pr e g n a n c y t est   will  b e  p erf or  m e d  at  r a n d o  mi z ati o n (  Visit  3, s e e 
T a bl e   2). R es ults   m ust  b e  n e g ati v e f or i niti al st u d y  eli gi bilit y  a n d  c o nti n u e d  p arti ci p ati o n.   A 
p ositi v e  pr e g n a n c y t e st r es ult  at  a n y ti  m e   will  n e c essit at e t h e s u bj e ct’s i  m  m e di at e   wit h dr a  w al 
fr o  m t h e st u d y.   A d diti o n al f oll o  w- u p   m a y  b e r e q uir e d  as  d et ail e d i n S e cti o n  8. 4. 1 . 




 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  3 5  of  6 7 
•    A S T  or   A L T  > 3 × U L  N;  c o nfir  m e d  b y r e p e at t esti n g    as s o o n  as  p ossi bl e. If t h e  v al u e 
r e  m ai ns  > 3× U L  N f or  ≥ 2   w e e ks  aft er  dis c o nti n u ati o n  of st u d y tr e at  m e nt, t h e s u bj e ct 
m ust  p er  m a n e ntl y  dis c o nti n u e st u d y tr e at  m e nt   
•    L y  m p h o c yt e  c o u nt  < 0. 5 ×   1 09/ L;  c o nfir  m e d  b y r e p e at t esti n g  as s o o n  as  p ossi bl e. If 
t h e  v al u e r e  m ai ns  < 0. 5 ×   1 09/ L f or  ≥ 2   w e e ks  aft er  dis c o nti n u ati o n  of st u d y tr e at  m e nt, 
t h e s u bj e ct   m ust  p er  m a n e ntl y  dis c o nti n u e st u d y tr e at  m e nt 
•    Esti  m at e d  gl o  m er ul ar filtr ati o n r at e ( e  G F  R)  < 6 0   m L/  mi n/ 1. 7 3  m 2;  c o nfir  m e d  b y r e p e at 
t esti n g  as s o o n  as  p ossi bl e. If t h e  e  G F  R r e  m ai ns  < 6 0   m L/  mi n/ 1. 7 3  m2 f or  ≥ 2   w e e ks 
aft er  d is c o nti n u ati o n  of st u d y tr e at  m e nt, t h e s u bj e ct   m ust  p er  m a n e ntl y  dis c o nti n u e 
st u d y tr e at  m e nt 
•    Uri n e  al b u  mi n t o  uri n e  cr e ati ni n e r ati o  > 2  0 0  m g/ g;  c o nfir  m e d  b y r e p e at t esti n g   as 
s o o n  as  p ossi bl e. If t h e  uri n e  al b u  mi n t o  uri n e  cr e ati ni n e r ati o r e  m ai ns  > 2 0 0  m g/ g   f or 
≥ 2   w e e ks  aft er  dis c o nti n u ati o n  of st u d y tr e at  m e nt, t h e s u bj e ct   m ust  p er  m a n e ntl y 
dis c o nti n u e st u d y tr e at  m e nt 
R es u  mi n g   st u d y dr u g  tr e at  m e nt  aft er it  h as  b e e n   wit h h el d is t o  b e  c o nsi d er e d  o n  a  c as e  b y  c as e 
b asis  a n d   m ust  b e  dis c uss e d   wit h t h e   M e di c al  M o n  it or. 
8. 4. 1.    
C o nt r a c e pti o n  a n d  P r e g n a n c y   
All   m al e  a n d f e  m al e s u bj e cts   m ust  a gr e e t o t h e  us e  of t  w o   m et h o ds  of  c o ntr a c e pti o n f or t h e 
d ur ati o n  of t h e st u d y  a n d  3 0  d a ys  aft er t h e fi n al  d os e  of st u d y  dr u g.  T his i n cl u d es  at l e ast  o n e 
f or  m  of  hi g hl y  eff e cti v e   m et h o d  of  c o ntr a c e pti o n  a n d  o n e  a c c e pt a bl e   m et h o d  of  c o ntr a c e pti o n 
( a n d  a d diti o n al r estri cti o ns, if r e q uir e d,   will  b e  cl arifi e d i n t h e l o c all y  a p pr o v e d i nf or  m e d  c o ns e nt 
f or  m [I C F]).  S u bj e cts   w h o  ar e  a bsti n e nt  ar e  eli gi bl e,  pr o vi d e d t h e y  a gr e e t o t h e  us e  of t  w o 
c o ntr a c e pti v e   m et h o ds ( at l e ast  o n e  b ei n g  a  hi g hl y  eff e cti v e   m et h o d) s h o ul d t h e y  b e c o  m e 
s e x u all y  a cti v e.  
Hi g hl y  eff e cti v e   m et h o ds   m a y i n cl u d e  : 
•    Or al, i ntr a v a gi n al,  or tr a ns d er  m al  c o  m bi n e d ( estr o g e n  a n d  pr o g est o g e n  c o nt ai ni n g) 
h or  m o n al  c o ntr a c e pti o n  ass o ci at e d   wit h i n hi biti o n  of  o v ul ati o n ( or al  c o ntr a c e pti v es 
m ust  h a v e  b e e n i niti at e d  at l e ast  3 0  d a ys  pri or t o s cr e e ni n g) 
•    Or al, i nj e ct a bl e,  or i  m pl a nt a bl e  pr o g est o g e n  - o nl y  h or  m o n al  c o ntr a c e pti o n  ass o ci at e d 
wit h i n hi biti o n  of  o v ul ati o n ( or al  c o ntr a c e pti v es   m ust  h a v e  b  e e n i niti at e d  at l e ast 
3 0  d a ys  pri or t o s cr e e ni n g) 
•    I ntr a ut eri n e  d e vi c e 
•    I ntr a ut eri n e  h or  m o n e-r el e asi n g s yst e  m 
•    Bil at er al t u b al  o c cl usi o n   
•    V as e ct o  mi z e d  p art n er ( pr o vi d e d t h at  p art n er is s ol e s e x u al  p art n er  of s u bj e ct  a n d 
p art n er  h as r e c ei v e d   m e di c al  ass ess  m e nt  of s ur gi c al s u c c ess)  
•    S e x u al  a bsti n e n c e ( d efi n e d  as r efr ai ni n g fr o  m  h et er os e x u al i nt er c o urs e  d uri n g t h e 
e ntir e st u d y  p eri o d t hr o u g h  at l e ast  3 0  d a ys  aft er t h e fi n al  d os e  of st u d y  dr u g) 




 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  3 7  of  6 7 
S y  m pt o  m ati c t h er a p y, s u c h  as tr e at  m e nt f or s p asti cit y,  d e pr essi o n  or f ati g u e is  n ot  pr o hi bit e d  b ut 
s h o ul d  b e  o pti  mi z e d  as  e arl y  as  p ossi bl e  aft er s cr e e ni n g i n  a n  att e  m pt t o   m ai nt ai n  c o nsist e nt 
tr e at  m e nt  d uri n g t h e st u d y. 
I  m  m u ni z ati o ns  usi n g i n a cti v at e d,  kill e d,  or  vir al  p arti cl e  v a c ci n es ( e g, i nfl u e n z a  v a c ci n e)  ar e 
p er  mitt e d  a n d  c a n  b e  a d  mi nist er e d  a c c or di n g t o I n v esti g at or j u d g  m e nt.   V a c ci n es  usi n g li v e  or 
att e n u at e d  vir us es  s h o ul d  n ot  b e  a d  mi nist er e d  u nl ess  a p pr o v e d  b y t h e   M e di c al   M o nit or. 
S u bj e cts s h o ul d  b e i nstr u ct e d  n ot t o st art t a ki n g  a n y  n e  w   m e di c ati o ns, i n cl u di n g  n o n- pr es cri b e d 
dr u gs,  u nl ess t h e y  h a v e r e c ei v e d  p er  missi o n fr o  m t h e I n v esti g at or. 
S e e  S e cti o n  8. 3. 5  f or  d et ails r e g ar di n g t h e  c o n c o  mit a nt m e di c ati o n r e vi e  w  . 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N  TI  A L  
P a g e  3 8  of  6 7 
9.    
T  R  E  A  T  M  E  N  T   O F  S  U  B J  E  C  T  S 
9. 1.    
St u d y   D r u g   D os e  a n d   A d  mi nist r ati o n  
C a ps ul es   will  b e  a d  mi nist er e d  or all y,   BI  D  . St u d y st aff   will  a d  mi nist er t h e first  d os e  of st u d y  dr u g 
at   Visit  3 ( R a n d o  mi z ati o n  ).  Fr o  m t h at  p oi nt  o n  d uri n g t h e tr e at  m e nt  p eri o d, a c c or di n g t o t h e 
s c h e d ul e  of  visits s h o  w n i n  T a bl e   2, t h e st aff   will  dis p e ns e st u d y  dr u g f or s u bj e cts’ 
s elf-a d  mi nistr ati o n .  S u bj e cts   will t a k e t  w o  c a ps ul es  of  bli n d e d st u d y  dr u g   BI  D  d uri n g t h e  5-w e e k 
d o u bl e- bli n d tr e at m e nt  p eri o d    as s h o  w n i n T a bl e   4.  Pl a c e b o  c a ps ul es  ar e i n cl u d e d i n  or d er t o 
k e e p t h e  n u  m b er  of  c a ps ul es  at  e a c h  a d  mi nistr ati o n   c o nsist e nt  b et  w e e n tr e at  m e nt  gr o u ps t o 
m ai nt ai n t h e st u d y  bli n d  . S u bj e cts   will  b e i nstr u c t e d t o t a k e  b ot h  c a ps ul es si  m ult a n e o usl y f or 
b ot h   m or ni n g  a n d  e v e ni n g  d os es. 
S u bj e cts   will  b e i nstr u ct e d t o t a k e st u d y  dr u g  wit h  or   wit h o ut f o o d.   H o  w e v er  , s u bj e cts   will  b e 
i nstr u ct e d t o  a v oi d t a ki n g st u d y  dr u g   wit h  a  hi g h-f at,  hi g h-c al ori e   m e al.    Det ail e d  d osi n g 
i nstr u cti o ns   will  b e  pr o vi d e d t o t h e  p ati e nts  b y t h e sit e  p ers o n n el.  
N o  d os e r e d u cti o ns   will  b e  p er  mitt e d  d uri n g t h e st u d y. If  a s u bj e ct  d o es  n ot t ol er at e t h e st u d y 
dr u g  d uri n g t h e i niti al  1 -  w e e k  d os e titr ati o n  p eri o d  or  aft er t h e  d os e titr ati o n  p eri o d, t h e s u bj e ct 
will  b e  dis c o nti n u e d fr o  m t h e st u d y. 
T a bl e  4:   
St u d y   D r u g   D osi n g  S c h e d ul e  ( P a rt   A  a n d  P a rt   B) 
Bli n d e d   T r e at  m e nt   G r o u p   
W e e k  1   (  Tit r ati o n) 
(  D a ys  1-7;  4  c a ps ul es  p e r  d a y)  
W e e ks  2  - 5 
(  D a ys  8- 3 5,  4  c a ps ul es  p e r  d a y) 
A L  K S  8 7 0 0  4 6 2   m g   BI  D  
( T ot al  d ail y  d os e:  9 2 4  m g)  
M or ni n g:  1    c a ps ul e  of  2 3 1  m g, 
1  c a ps ul e  of  pl a c e b o  
M or ni n g:  2    c a ps ul es  of  2 3 1  m g  
 
E v e ni n g:  1   c a ps ul e  of  2 3 1  m g, 
1  c a ps ul e  of  pl a c e b o  
E v e ni n g:  2   c a ps ul es  of  2 3 1  m g  
D  M F  2 4 0   m g   BI  D    
( T ot al  d ail y  d ose:  4 8 0   m g)   
M or ni n g:  1     c a ps ul e  of  1 2 0 m g, 
1  c a ps ul e  of  pl a c e b o  
E v e ni n g:  1  c a ps ul e  of  1 2 0  m g, 
1  c a ps ul e  of  pl a c e b o  
M or ni n g:  1     c a ps ul e  of  2 4 0 m g, 
1  c a ps ul e  of  pl a c e b o  
E v e ni n g:  1  c a ps ul e  of  2 4 0  m g, 
1  c a ps ul e  of  pl a c e b o  
9. 2.    
T r e at  m e nt   A d h e r e n c e   
A c c or di n g t o t h e   s c h e d ul e i n T a bl e   2,  at  e a c h s p e cifi e d  dis p e nsi n g  visit, s u bj e cts   will r e c ei v e  a 
s u p pl y  of st u d y  dr u g  t o l ast  u ntil t h e f oll o  wi n g  visit.  S u bj e cts   will  b e i nstr u ct e d t o  bri n g  a n y 
u n us e d  st u d y dr u g  a n d t h e  b ottl e(s)   wit h t h e  m t o  e a c h s u bs e q u e nt  visit.  St u d y  d r u g  a d h er e n c e 
will  b e r e vi e  w e d   wit h s u bj e cts  at  e a c h  visit.   
9. 3.    
R a n d o  mi z ati o n/  M et h o d  of   Assi g ni n g  S u bj e cts t o   T r e at  m e nt   
S e p ar at e r a n d o  mi z ati o n s c h e d ul es   will  b e  pr e p ar e d f or  P art   A  a n d f or  P art   B   of t h e st u d y.   O n c e 
P ar t   A  of t h e st u d y is  c o  m pl et e d (i e, t h e l ast s u bj e ct  h as  c o  m pl et e d t h e l ast  visit  i n P art   A ), t h e 
d at a b as e f or  P art   A   will  b e l o c k e d  a n d   u n bli n d e d,  a n d a n  a n al ys is of t h e  P art   A  d at a  will  b e 






 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  4 1  of  6 7 
1 0.    
S  T  U  D  Y   D  R  U  G   M  A  T  E  RI  A  L S    AN  D   M  A  N  A  G  E  M  E  N  T   
1 0. 1.    
St u d y   D r u g  
1 0. 1. 1.    
A  L  K S  8 7 0 0 
I n v esti g ati o n al  pr o d u ct f or t his st u d y is   A L  K S  8 7 0 0,  pr o vi d e d  as  c a ps ul es f or  or al 
a d  mi nistr ati o n.   A L  K S  8 7 0 0 i n v esti g ati o n al  pr o d u ct  c o nsists  of  d el a y e d- r el e as e (  D  R) ( e nt eri c–
c o at e d)   mi nit a bl ets  c o nt ai n e d   wit hi n  a  h y dr o x y pr o p yl   m et h yl c ell ul os e (  H P  M  C)  c a ps ul e.  T h e 
d os es  of   A L  K S  8 7 0 0 t o  b e  us e d i n t his st u d y  ar e  2 3 1   m g ( a d  mi nist er e d  as  o n e  c a ps ul e  d uri n g 
W e e k  1 [ d os e titr ati o n])  a n d  4 6 2   m g ( a d  mi nist er e d  as t  w o  2 3 1   m g  c a ps ul es  d uri n g   W e e ks  2-  5). 
C a ps ul es   will  b e  a d  mi nist er e d   or all y, t  wi c e  p er  d a y.  
1 0. 1. 2.    
Di  m et h yl  F u  m a r at e   
R ef er e n c e t h er a p y f or t his st u d y is  c o  m  m er ci all y  a v ail a bl e   D  M F ( T e cfi d er a;   m a n uf a ct ur e d  b y 
Bi o g e n I n c.  of   C a  m bri d g e,   M  A)  c a ps ul es f or  or al  a d  mi nistr ati o n.   T h e   D  M F  c a ps ul es   will  b e 
o v er- e n c a ps ul at e d i n t h e s a  m e   H P  M  C  c a ps ul e  us e d f or t h e   A L  K S  8 7 0 0  dr u g  pr o d u ct t o  cr e at e 
bli n d e d st u d y  dr u g.  T h e  d os es  of   D  M F t o  b e  us e d i n t his st u d y  ar e  1 2 0   m g ( a d  mi nist er e d  as  o n e 
c a ps ul e  d uri n g   W e e k  1 [ d os e titr ati o n])  a n d  2 4 0   m g ( a d  mi nist er e d  as  o n e  c a ps ul e  d uri n g 
W e e ks    2- 5).   C a ps ul es will  b e  a d  mi nist er e d  or all y, t  wi c e  p er  d a y.   
1 0. 1. 3.    
Pl a c e b o  
Pl a c e b o  c a ps ul es  ar e i n cl u d e d i n t his st u d y i n  or d er t o  k e e p t h e  n u  m b er  of  c a ps ul es  at  e a c h  or al 
a d  mi nistr ati o n  c o nsist e nt  b et  w e e n tr e at  m e nt  gr o u ps t o   m ai nt ai n t h e st u d y  bli n d.  T h e  pl a c e b o 
m at c h e d t o   t h e A L  K S  8 7 0 0  a n d   D  M F  dr u g  pr o d u cts   will   c o nsist  of  pl a c e b o   mi nit a bl ets  c o nt ai n e d 
wit hi n t h e s a  m e   H P  M  C  c a ps ul e  us e d f or t h e   A L  K S  8 7 0 0  dr u g  pr o d u ct  a n d  us e d t o  o v er-
e n c a ps ul at e t h e   D  M F  dr u g  pr o d u ct.  Pl a c e b o  c a ps ul es   will  b e  a d  mi nist er e d  or all y, t  wi c e  p er  d a y. 
1 0. 2.    
P a c k a gi n g  a n d   L a b eli n g  
A L  K S  8 7 0 0 ( 2 3 1   m g)   a n d  Pl a c e b o  c a ps ul es  ar e s u p pli e d i n  b ot h  2 0  c o u nt,  1 0 0  c c, i n d u cti o n 
s e al e d   H  D P E  b ottl es  a n d  6 4  c o u nt,  1 5 0  c c, i n d u cti o n s e al e d,   H  D P E  b ottl e  c o nfi g ur ati o n. 
L a b eli n g   will   m e et  all  a p pli c a bl e l o c al  a n d r e g ul at or y r e q uir e  m e nts.   Al k er  m es   will  p a c k a g e  a n d 
distri b ut e   A L  K S  8 7 0 0,   D  M F,  a n d  m at c hi n g   pl a c e b o  c a ps ul es t o t h e  cli ni c al sit e.  
1 0. 3.    
St o r a g e  
All st u d y   m at eri als  ar e t o  b e st or e d  at r o o  m t e  m p er at ur e   n ot t o  e x c e e d  2 5°  C elsi us   i n  a s e c ur e 
l o c ati o n.   D  M F   will  b e st or e d i n  a c c ord a n c e   wit h t h e   m a n uf a ct ur er’s s p e cifi c ati o ns.  
1 0. 4.    
A c c o u nt a bilit y   
T h e  cli ni c al sit e is r e q uir e d t o   m ai nt ai n  c urr e nt  dr u g  dis p e ns ati o n  a n d  a c c o u nt a bilit y l o gs 
t hr o u g h o ut t h e st u d y.   All  u n us e d s u p pli es   will  b e  c h e c k e d  a g ai nst t h e  dr u g   m o v e  m e nt r e c or ds 
d uri n g t h e st u d y  a n d/ or  at t h e  e n d  of t h e st u d y. 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  4 2  of  6 7 
R ef er t o   S e cti o n  9  f or  a d diti o n al st u d y  dr u g r e c o n cili ati o n  pr o c e d ur es. 
1 0. 5.    
H a n dli n g  a n d   Dis p os al   
T h e  cli ni c al sit e is r e q uir e d t o   m ai nt ai n  c urr e nt  dr u g  dis p e ns ati o n  a n d  a c c o u nt a  bilit y l o gs 
t hr o u g h o ut t h e st u d y.  F oll o  wi n g  c o  m pl eti o n  a n d  v erifi c ati o n  of  a c c o u nt a bilit y l o gs,  all  u n us e d 
a n d  us e d  p a c k a g es   m ust  b e  d estr o y e d.  P a c k a g es   m a y  b e  d estr o y e d  o n sit e  a c c or di n g t o   G o o d 
Cli ni c al  Pr a cti c e (  G  C P)  a n d sit e  pr a cti c e.   Alt er n ati v el y, t h  e s p o ns or   m a y  arr a n g e f or  d estr u cti o n 
wit h  a t hir d  p art y  v e n d or  o p er ati n g i n  a c c or d a n c e   wit h   G  C P  a n d/ or   G o o d   M a n uf a ct uri n g  Pr a cti c e 
(  G  M P),  as  a p pli c a bl e. 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  4 3  of  6 7 
1 1.    
A S S  E S S  M  E  N  T   O F  S  A F  E  T  Y   A  N  D   T  O  L  E  R  A  BI  LI  T  Y   
S af et y  a n d t ol er a bilit y t hr o u g h o ut t h e st u d y  will  b e  ass ess e d   us i n g t h e f oll o  wi n g: 
•    I  GI SI S 
•    G  GI SI S   
•    A Es   
•    Vit al si g ns ( or al t e  m p er at ur e, r es pir at or y r at e,  h e art r at e  ,  a n d  bl o o d  pr ess ur e) 
•    Cli ni c al l a b or at or y  p ar a  m et ers ( bl o o d  bi o c h e  mistr y,  h e  m at ol o g y,  uri n al ysis [i n cl u di n g 
uri n e  al b u  mi n,  uri n e  b et a- 2-  mi cr o gl o b uli n,  a n d  uri n e  cr e ati ni n e ]) 
•    E  C  G  p ar a  m et ers ( u n c orr e ct e d   Q T,   Q T c F,   Q T c  B,  P  R,   R  R,  a n d   Q  R S i nt er v als) 
•    C-  S S  R S  
1 1. 1.    
D efi niti o n  of   A d v e rs e   E v e nt   
A n   A E is  a n y  u nt o  w ar d   m e di c al  o c c urr e n c e i n  a  p ati e nt  or  cli ni c al i n v esti g ati o n s u bj e ct 
a d  mi nist er e d  a  p h ar  m a c e uti c al  pr o d u ct.  T h e  o c c urr e n c e,   w hi c h   m a y  or   m a y  n ot  h a v e  a  c a us al 
r el ati o ns hi p   wit h t h e i n v esti g ati o n al tr e at  m e nt,   m a y i n cl u d e  a n y  cli ni c al  or l a b or at or y  c h a n g e t h at 
d o es  n ot  c o  m  m o nl y  o c c ur i n t h at s u bj e ct  a n d is  c o nsi d er e d  cli ni c all y si g nifi c a nt. 
Ill n ess es  pr es e nt  pri or t o t h e su bj e ct si g ni n g t h e I  C F  ar e  c o nsi d er e d t o  b e  pr e e xisti n g  c o n diti o ns 
a n d  ar e  d o c u  m e nt e d  o n t h e   m e di c al  hist or y  e  C  R F.  Pr e- e xisti n g  c o n diti o ns t h at   w ors e n  d uri n g t h e 
st u d y  ar e  e nt er e d  o n t h e   A E  e  C  R F.  
All  o ut- of-  r a n g e l a b or at or y  v al u es   will  b e  d e e  m e d  as  cli ni c all y si g nifi c a nt  or  n ot  cli ni c all y 
si g nifi c a nt  b y t h e  I n v esti g at or.   Cli ni c all y si g nifi c a nt  v al u es   will  b e  c o nsi d er e d   A Es  a n d r e c or d e d 
as s u c h  o n t h e  e  C  R Fs. 
Pr e g n a n c y is  n ot  c o nsi d er e d  a n   A E,  alt h o u g h  a s u bj e ct   will  b e   wit h dr a  w n fr o  m t h e st u d y if  a 
pr e g n a n c y  o c c urs.   As  d es cri b e d i n  S e cti o n  8. 4. 1 , t h e  pr e g n a n c y   m ust  b e r e p ort e d t o   Al k er  m es 
a n d  a d diti o n al f oll o  w- u p   m a y  b e r e q uir e d. 
1 1. 2.    
D efi niti o n  of  S e ri o us   A d v e rs e   E v e nt   
A n  S  A E is  a n y   A E,  o c c urri n g  at  a n y  d os e  a n d r e g ar dl  ess  of  c a us alit y t h at  r es ults i n  o n e  or   m or e 
of t h e f oll o  wi n g: 
•    R es ults i n  d e at h   
•    Is lif e-t hr e at e ni n g.  T h e s u bj e ct is  at i  m  m e di at e ris k  of  d e at h fr o  m t h e r e a cti o n  as it 
o c c urs.  T his  d o es  n ot i n cl u d e r e a cti o n t h at,  h a d it  o c c urr e d i n  a   m or e s e v er e f or  m, 
mi g ht   h a v e  c a us e d  d e at h  
•    R e q uir es i n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n.   H os pit al 
a d  missi o n f or  el e cti v e s ur g er y s c h e d ul e d  pri or t o st u d y  e ntr y is  n ot  c o nsi d er e d  a n 
S  A E  


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  4 4  of  6 7 
•    R es ults i n  dis a bilit y/i n c a p a cit y ( e g,  a s u bst a nti al  disr u pti o  n  of  a  p ers o n’s  a bilit y t o 
c o n d u ct  n or  m al lif e f u n cti o ns) 
•    Is  a  c o n g e nit al  a n o  m al y/ birt h  d ef e ct 
I  m p ort a nt   m e di c al  e v e nts t h at   m a y  n ot r es ult i n  d e at h,  b e i  m  m e di at el y lif e t hr e at e ni n g,  or r e q uir e 
h os pit ali z ati o n   m a y  b e  c o nsi d er e d t o  b e  S  A Es   w h e n,  b as e d  u p o n  a p pr o pri at e   m e di c al j u d g  m e nt, 
t h e y   m a y j e o p ar di z e t h e  p ati e nt  or s u bj e ct  a n d   m a y r e q uir e i nt er v e nti o n t o  pr e v e nt  o n e  of t h e 
ot h er  o ut c o  m es list e d  a b o v e. 
1 1. 3.    
R el ati o ns hi p t o  St u d y   D r u g   
T h e  ass ess  m e nt  of st u d y  dr u g r el ati o ns hi p t o  e a c h   A E   will  b e r e p ort e d  o n t h e  a p pr o pri at e s o ur c e 
d o c u  m e nt ( a n d  S  A E f or  m, i n t h e  e v e nt  of  a n  S  A E)  b y t h e I n v esti g at or ( or  d esi g n at e d 
S u b-I n v esti g at or )  a c c or di n g t o  his/ h er  b est  cli ni c al j u d g  m e nt.  T h e  crit eri a list e d i n T a bl e   5 
s h o ul d  b e  us e d t o g ui d e t his  ass ess  m e nt.  Pl e as e  n ot e t h at  n ot  all  crit eri a   m ust  b e  pr es e nt t o  b e 
i n di c ati v e  of  a  p arti c ul ar  dr u g r el ati o ns hi p.   All st u d y  dr u gs  ar e  c o nsi d er e d  “t est  dr u gs ” f or t h e 
p ur p os es  of t h e  d efi niti o ns list e d i n t h e t a bl e. 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  4 5  of  6 7 
T a bl e  5:   
A d v e rs e   E v e nt   C a us alit y   G ui d eli n es   
R el ati o ns hi p     
C rit e ri a f o r  ass ess  m e nt   
D efi nit el y  r el at e d   T h er e is  e vi d e n c e  of  e x p os ur e t o t h e t est  dr u g.  
A  N  D   
T h e t e  m p or al s e q u e n c e  of t h e   A E  o ns et r el ati v e t o  a d  mi nistr ati o n  of t h e t est  dr u g is 
r e as o n a bl e. 
T h e   A E is   m or e li k el y  e x pl ai n e d  b y t h e t est  dr u g t h a n  b y  a n ot h er  c a us e. 
D e c h all e n g e (if  p erf or  m e d) is  p ositi v e.   
R e c h all e n g e (if f e asi bl e) is  p ositi v e.   
T h e   A E s h o  ws  a  p att er n  c o nsist e nt   wit h  pr e vi o us  k n o  wl e d g e  of t h e t est  dr u g  or t est 
dr u g  cl ass.  
P r o b a b l y  r el at e d 
T h er e is  e vi d e n c e  of  e x p os ur e t o t h e t est  dr u g.  
A  N  D   
T h e t e  m p or al s e q u e n c e  of t h e   A E  o ns et r el ati v e t o  a d  mi nistr ati o n  of t h e t est  dr u g is 
r e as o n a bl e. 
T h e   A E is   m or e li k el y  e x pl ai n e d  b y t h e t est  dr u g t h a n  b y  a n ot h er  c a us e. 
D e c h all e n g e (if  p erf or  m e d) is  p ositi v e.   
P ossi bl y  r el at e d  
T h er e is  e vi d e n c e  of  e x p os ur e t o t h e t est  dr u g.  
A  N  D   
T h e t e  m p or al s e q u e n c e  of t h e   A E  o ns et r el ati v e t o  a d  mi nistr ati o n  of t h e t est  dr u g is 
r e as o n a bl e. 
T h e   A E  c o ul d  h a v e  b e e n  d u e t o  a n ot h er  e q u all y li k el y  c a us e. 
D e c h all e n g e (if  p erf or  m e d) is  p ositi v e.   
P r o b a bl y  n ot 
r el at e d  
T h er e is  e vi d e n c e  of  e x p os ur e t o t h e t est  dr u g.  
A  N  D   
T h er e is  a n ot h er   m or e li k el y  c a us e  of t h e   A E.  
D e c h all e n g e (if  p erf or  m e d) is  n e g ati v e  or  a  m bi g u o us.   
R e c h all e n g e (if  p erf or  m e d) is  n e g ati v e  or  a  m bi g u o us.   
D e  fi nit el y  n ot 
r el at e d  
T h e s u bj e ct  di d  n ot r e c ei v e t h e t est  dr u g.  
O  R   
T e  m p or al s e q u e n c e  of t h e   A E  o ns et r el ati v e t o  a d  mi nistr ati o n  of t h e t est  dr u g is  n ot 
r e as o n a bl e.  
O  R   
T h er e is  a n ot h er  o b vi o us  c a us e  of t h e   A E.  


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  4 6  of  6 7 
1 1. 4.    
M o nit o ri n g  a n d   R e c o r di n g  of   A d v e rs e   E v e nts   
A E   d at a  c oll e cti o n   will  b e gi n  aft er  a s u bj e ct si g ns t h e I C F   a n d   will  c o nti n u e  u ntil  c o  m pl eti o n  of 
t h e s af et y f oll o  w-u p  visit (  Visit  9) .   A n y   A E  or S  A E  h a vi n g  a n  o ns et  aft er t h e s af et y f oll o  w - u p 
visit   will  n ot  b e  c oll e ct e d  or r e p ort e d  u nl ess t h e i n v esti g at or  fe els t h at t h e  e v e nt   m a y  b e r el at e d t o 
t h e st u d y  dr u g. 
S u bj e cts   will  b e i nstr u ct e d  b y t h e  I n v esti g at or  or  d esi g n e e t o r e p ort t h e  o c c urr e n c e  of  a n y   A E. 
All  v ol u nt e er e d,  eli cit e d,  a n d  o bs er v e d   A Es  ar e t o  b e r e c or d e d  o n t h e   A E  e  C  R Fs. 
T h e  I n v esti g at or will  ass e  ss  all   A Es r e g ar di n g  a n y  c a us al r el ati o ns hi p t o t h e st u d y  dr u g (s e e 
S e cti o n  1 1. 3 ), t h e i nt e nsit y (s e v erit y)  of t h e  e v e nt,  a cti o n t a k e n,  a n d s u bj e ct  o ut c o  m e. 
T h e f oll o  wi n g  crit eri a s h o ul d  b e  us e d t o  g ui d e t h e  ass e ss  m e nt  of i nt e nsit y (s e v erit y):  
•    Mil d:     C a us es  a  w ar e n ess  of si g n  or s y  m pt o  m,  b ut is  e asil y t ol er at e d;  d o es  n ot i nt erf er e 
wit h  us u al  a cti viti es   
•    M o d e r at e:   C a us es  dis c o  mf ort  e n o u g h t o i nt erf er e   wit h  us u al  a cti viti es   
•    S e v e r e:  Is i n c a p a cit ati n g; r es ults i n i n a bilit y t o   w or k  or  p erf or  m  us u al  a cti viti es 
All   A Es   will  b e f oll o  w e d  u ntil r es ol uti o n,  u ntil  d e e  m e d st a bl e  b y t h e I n v esti g at or  ,  or  u ntil t h e 
s u bj e ct is  d e e  m e d  b y t h e  I n v esti g at or t o  b e l ost t o f oll o  w- u p. 
F or  cli ni c al st u d y s af et y r e p orti n g  p ur p os es, t h e   m ost r e c e nt  v ersi o n  of t h e I n v esti g at or’s 
Br o c h ur e   will  b e  us e d  as t h e r ef er e n c e  d o c u  m e nt t o  d esi g n at e  e v e nt  e x p e ct e d n ess.   
Wit h dr a  w al fr o  m t h e st u d y  as  a r es ult  of  a n   A E  a n d  a n y t h er a p e uti c   m e as ur es t h at  ar e t a k e n s h all 
b e  at t h e  dis cr eti o n  of t h e I n v esti g at or . If  a s u bj e ct   wit h dr a  ws fr o  m t h e st u d y f or  a n y r e as o n,  a n y 
o n g oi n g   A Es   will  b e f oll o  w e d  u ntil r es ol uti o n,  u ntil  d e e  m e d st a bl e  b y t h e i n v esti g at or,  or  u ntil 
t h e s u bj e ct is  d e e  m e d  b y t h e I n v esti g at or t o  b e l ost t o f oll o  w- u p. 
1 1. 5.    
R e p o rti n g  of  S e ri o us   A d v e rs e   E v e nts   
All  S  A Es   m ust  b e r e p ort e d t o   Al k er  m es   Dr u g  S af et y   vi a 
   wit hi n  1  b usi n ess  d a y  of 
dis c o v er y,  b y f a xi n g t h e r e p ort t o t h e f oll o  wi n g:  
Att e nti o n:   
 
E  m ail: 
 
P h o n e   N u  m b e r:  
 
F  A  X   N u  m b e r .: 
 
T h e   writt e n r e p ort s h o ul d  b e s u b  mitt e d  o n t h e  S  A E f or  m  pr o vi d e d f or t his  p ur p os e.  T h e r e p ort 
m ust i n cl u d e t h e i n v esti g at or  ’s o pi ni o n  as t o   w h et h er t h e  e v e nt is st u d y  dr u g- r el at e d. If t his 
r el ati o ns hi p is  d et er  mi n e d t o  b e  p ossi bl y,  pr o b a bl y,  or  d efi nit el y r el at e d t o st u d y  dr u g,  e vi d e n c e 
t o s u p p ort t his  ass ess  m e nt   m ust  als o  b e  pr o vi d e d. 








 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  5 0  of  6 7 
1 4. 3. 2.    
S e c o n d a r y   E n d p oi nts  
•    A  U  C f or t h e t ot al I  GI SI S s y  m pt o  m i nt e nsit y s c or e r el ati v e t o  e x p os ur e  d a ys i n  P art   B   
•    N u  m b er  of  d a ys   wit h  a   G  GI SI S s y  m pt o  m i nt e nsit y s c or e  ≥ 3 r el ati v e t o  e x p os ur e  d a ys 
i n  P art   B. 
T h e  pri  m ar y  a n d s e c o n d ar y  e n d p oi nts   m a y  b e   m o difi e d  b as e d  o n  d at a  o bt ai n e d fr o  m  P art   A. 
1 4. 4.    
D e  m o g r a p hi cs  a n d   B as eli n e   C h a r a ct e risti cs   
S u  m  m ar y st atisti cs   will  b e  pr o vi d e d f or  all  d e  m o gr a p hi c  v ari a bl es  a n d  b as eli n e  c h ar a ct eristi cs  b y 
tr e at  m e nt  gr o u p  a n d  o v er all.   M e di c al  hist or y   will  b e s u  m  m ari z e d f or t h e s af et y  p o p ul ati o n  usi n g 
t h e  n u  m b er  of  o bs er v ati o ns  a n d  p er c e nt a g e  of s u bj e cts r e p orti n g  e a c h  c at e g or y b y tr e at  m e nt 
gr o u p  a n d  o v er all. 
1 4. 5.    
S af et y   A n al ys es  ( P a rt   A  a n d  P a rt   B) 
All  a n al ys es   will  b e  c arri e d  o ut  usi n g t h e r es p e cti v e s af et y  p o p ul ati o ns   f or  P art   A  a n d  P art   B 
s e p ar at el y.  F or  e a c h s af et y  p ar a  m et er,  b as eli n e is  d efi n e d  as t h e l ast  n o n -missi n g  ass ess  m e nt 
pri or t o t h e first  d os e  of st u d y  dr u g. 
S af et y   will  b e  e v al u at e d  b as e d  o n t h e  o c c urr e n c e  of   A Es,  vit al si g ns, r es ult s  of  cli ni c al l a b or at or y 
t ests,  a n d  E  C  G fi n di n gs.   R e p ort e d A E   t er  ms   will  b e  c o d e d  usi n g t h e   M e di c al   Di cti o n ar y f or 
R e g ul at or y   A cti viti es (  M e d  D  R  A  ,  v ersi o n  1 7). 
Tr e at  m e nt -e  m er g e nt  a d v ers e  e v e nts ( T E  A Es ) ar e  d efi n e d  as   A Es t h at  o c c ur  or   w ors e n  aft er t h e 
first  d os e  of st u d y  dr u g. 
S af et y  ass ess  m e nts   will  b e s u  m  m ari z e d  usi n g  d es cri pti v e st atisti cs  al o n g   wit h s u p p orti v e listi n gs 
b as e d  o n  o bs er v e d  v al u es.  Listi n gs   will  b e  pr o vi d e d f or  all s af et y  p ar a  m et ers.   T h e  n u  m b er  a n d 
p er c e nt a g e  of  T E  A Es   will  b e s u  m  m ari z e d  b y t r e at  m e nt  gr o u p  a n d  o v er all  b y s yst e  m  or g a n  cl ass, 
a n d  pr ef err e d t er  ms   wit hi n  e a c h s yst e  m  or g a n  cl ass.  S  A Es  a n d  T E A Es r es ulti n g i n tr e at  m e nt 
dis c o nti n u ati o n   will  als o  b e s u  m  m ari z e d.  
O bs er v e d  v al u es  a n d  c  h a n g e fr o  m  b as eli n e i n  cli ni c al l a b or at or y  p ar a  m et ers,  vit al si g ns,  E  C  G  
p ar a  m et ers,  a n d s c or es  o n t h e   C -S S  R S  will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  visit   f or  e a c h 
p art  of t h e st u d y.  T h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h s ui ci d al i d e ati o n  or  b e h a vi or  as 
ass ess e d  b y t h e   C -S S  R S   will  als o  b e s u  m  m ari z e d  b y  tr e at  m e nt  gr o u p.  T h e  n u  m b er  a n d 
p er c e nt a g e  of s u bj e cts   wit h  p ot e nti all y  cli ni c all y si g nifi c a nt ( P  C S)  v al u es  at  a n y  p ost- b as eli n e 
visit   will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p.  Listi n gs   will  b e  pr o vi d e d f or  all s af et y  e n d p oi nts. 
Pri or  a n d  c o n c o  mit a nt   m e di c ati o n  us e   will  b e  c o d e d  usi n g t h e   W orl d   H e alt h   Or g a ni z ati o n 
(  W  H  O) dr u g   A n at o  mi c al  T h er a p e uti c   C h e  mi c al (  A T  C)  cl assifi c ati o n s yst e  m.  Listi n gs   will  b e 
pr o vi d e d f or  all  pri or  a n d  c o n c o  mit a nt   m e di c ati o ns. 
A d diti o n al  d et ails  o n t h e s af et y  a n al ysis   will  b e  pr o vi d e  d i n t h e  St atisti c al   A n al ysis  Pl a n  ( S  A P) 
f or P art    A  a n d  P art   B. 






 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  5 3  of  6 7 
1 5.    
DI  R  E  C  T   A  C  C  E S S   T  O  S  O  U  R  C  E   D  A  T  A/  D  O  C  U  M  E  N  T S   
1 5. 1.    
St u d y   M o nit o ri n g  
M o nit ori n g  of t h e st u d y sit es (i n cl u di n g,  b ut  n ot li  mit e d t o, r e vi e  wi n g  e  C  R Fs f or  a c c ur a c y  a n d 
c o  m pl et e n ess)   will  b e  p erf or  m e d  b y  a n   Al k er  m es   m o nit or  or  d esi g n e e. 
1 5. 2.    
A u dits  a n d I ns p e cti o ns   
B y si g ni n g t h e  pr ot o c ol, t h e I n v esti g at or  a gr  e es t h at,   wit hi n l o c al r e g ul at or y r estri cti o ns  a n d 
i nstit uti o n al  a n d  et hi c al  c o nsi d er ati o ns,  a ut h ori z e d r e pr es e nt ati v es  of   Al k er  m es,  a r e g ul at or y 
a ut h orit y,  a n d/ or  a n I  R  B/  E  C   m a y  visit t h e sit e t o  p erf or  m  a u dits  or i ns p e cti o ns, i n cl u di n g t h e 
dr u g st or a g e  ar e a, st u d y  dr u g st o c ks,  dr u g  a c c o u nt a bilit y r e c or ds, s u bj e ct  c h arts  a n d s o ur c e 
d o c u  m e nts,  a n d  ot h er r e c or ds r el ati v e t o st u d y  c o n d u ct.  T h e  p ur p os e  of  a n   Al k er  m es  a u dit  or 
i ns p e cti o n is t o s yst e  m ati c all y  a n d i n d e p e n d e ntl y  e x a  mi n e  all st u d y-r el at e d  a cti viti es  a n d 
d o c u  m e nts ( e g, l a b or at or y r e p orts,  x-r a ys,   w or k b o o ks, s u bj e cts’   m e di c al r e c or ds) t o  d et er  mi n e 
w h et h er t h es e  a cti viti es   w er e  c o n d u ct e d,  a n d  d at a r e c or d e d,  a n al y z e d,  a n d  a c c ur at el y r e p ort e d 
a c c or di n g t o t h e  pr ot o c ol,   G  C P  g ui d eli n es  of t h e I nt er n ati o n al   C o nf er e n c e  o n   H ar  m o nis ati o n 
(I C  H),  a n d  a n y  a p pli c a bl e r e g ul at or y r e q uir e  m e nts. 
T h e  I n v esti g at or s h o ul d  c o nt a ct   Al k er  m es i  m  m e di at el y if  c o nt a ct e d  b y  a r e g ul at or y  a g e n c y 
r e g ar di n g  a n i ns p e cti o n. 
1 5. 3.    
I nstit uti o n al   R e vi e  w   B o a r d/I n d e p e n d e nt Et hi cs   C o  m  mitt e e   
T h e  I nv esti g at or  m ust  o bt ai n   I R  B/I E  C  a p pr o v al f or t h e i n v esti g ati o n. I niti al I R  B/IE  C  a p pr o v al  as 
w ell  as  all   m at eri als  a p pr o v e d  b y t h e   I  R  B/I E  C f or t his st u d y, i n cl u di n g t h e s u bj e ct  c o ns e nt f or  m 
a n d r e cr uit  m e nt   m at eri als,   m ust  b e   m ai nt ai n e d  b y t h e  I n v esti g at or a n d   m a d e  a v ail a bl e f or 
i ns p e cti o n. 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  5 4  of  6 7 
1 6.    
Q  U  A  LI  T  Y   C  O  N  T  R  O  L   A  N  D   Q  U  A  LI  T  Y   A S S  U  R  A  N  C  E   
T his st u d y   will  b e  c o n d u ct e d  u n d er   G  C P  a n d  all  a p pli c a bl e r e g ul at or y r e q uir e  m e nts.  T o  e ns ur e 
d at a  a c c ur a c y,  c o  m pl et e n ess  a n d  c o  m pli a n c e, t h e st u d y sit e s h o ul d  h a v e  pr o c ess es i n  pl a c e f o r 
d at a r e vi e  w  a n d  q u alit y  c o ntr ol.  Al k er  m es   m a y   als o  c o n d u ct  a  q u alit y  ass ur a n c e  a u dit.  Pl e as e s e e 
S e cti o n  1 5. 2  f or  d et ails r e g ar di n g t h e  a u dit  pr o c ess. 
1 6. 1.    
C as e   R e p o rt  F o r  ms    
T his st u d y   will  us e  e  C  R Fs.   All  e  C  R F  d at a    m ust  b e  b as e d  o n s o ur c e  d o c u  m e nts  or  a p pr o v e d t o  b e 
t h e  ori gi n al  d at a (i e,  d at a  dir e ctl y r e p ort e d  o n t h e  e  C  R F). All  e  C  R Fs   will  b e  c o  m pl et e d  b y t h e 
cli ni c st aff  pri or t o r e vi e  w  b y t h e   Al k er  m es   m o nit or  or  d esi g n at e d r e pr es e nt ati v e. 
T h e   Al k er  m es   m o nit or  or  d esi g n at e d r e pr es e nt ati v e   will r e vi e  w  all s o ur c e r e c or ds  o n -sit e  a n d 
c o  m p ar e t h e  m t o t h e  d at a  c oll e ct e d  o n t h e  e  C  R F.  
1 6. 2.    
C o nfi d e nti alit y  of   D at a   
B y si g ni n g t his  pr ot o c ol, t h e   i n v esti g at or  affir  ms t o   Al k er  m es t h at  h e  or s h e   will   m ai nt ai n i n 
c o nfi d e n c e i nf or  m ati o n f ur nis h e d t o  hi  m  or  h er  b y   Al k er  m es  a n d   will  di v ul g e s u c h i nf or  m ati o n 
t o  his  or  h er r es p e cti v e I  R  B  or I E  C  u n d er  a n  a p pr o pri at e  u n d erst a n di n g  of  c o nfi d e nti alit y   wit h 
s u c h  b o ar d.   All  d at a   will  b e  c o nsi d er e d t h e s ol e  pr o p ert y  of   Al k er  m es.  Pl e as e r ef er t o t h e   Cli ni c al 
St u d y   A gr e e  m e nt (  C S  A) f or  d et ails.  


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  5 5  of  6 7 
1 7.    
E  T  HI  C  A  L   C  O  N SI  D  E  R  A  TI  O  N S   
1 7. 1.    
Et hi cs   R e vi e  w   
T h e  cli ni c al sit e’s  I  R  B/IE  C   m ust   m e et  all r el e v a nt r e g ul at or y r e q uir e  m e nts.  T h e st u d y  pr ot o c ol 
a n d I C F   will  b e r e vi e  w e d  b y t h e  I  R  B/I E  C  pri or t o  e nr olli n g s u bj e cts i nt o t h e st u d y;   writt e n 
a p pr o v al fr o  m t h e  c o  m  mitt e e   m ust  b e r e c ei v e d  b y   Al k er  m es  b ef or e  dr u g   will  b e r el e as e d t o t h e  
I n v esti g at or.  T h e  pr ot o c ol   m ust  b e r e- a p pr o v e d  b y t h e I RB/  I E  C  u p o n r e c ei pt  of  a  m e n d  m e nts  a n d 
a n n u all y,  as l o c al r e g ul at or y r e q uir e  m e nts r e q uir e. 
T h e  I n v esti g at or is r es p o nsi bl e f or s u b  mitti n g  all  pr ot o c ol  c h a n g es  a n d  S  A E r e p orts t o t h e 
I  R  B/I E  C  a c c or di n g t o l o c al  pr o c e d ur es.   At  a   mi ni  m u  m,  all  S  A Es r e q uiri n g  a n i n v esti g ati o n al 
n e  w  dr u g s af et y r e p ort   m ust  b e i  m  m e di at el y r e p ort e d.  
All r el e v a nt  c orr es p o n d e n c e fr o  m t h e   I R  B/E  C   will  b e f or  w ar d e d  b y t h e r es p e cti v e st u d y sit e t o 
t h e s p o ns or i n  a ti  m el y f as hi o n. 
1 7. 2.    
Et hi c al   C o n d u ct  of t h e  St u d y   
T his st u d y   will  b e  c o n d u ct e d i n  a c c or d a n c e   wit h t h e  pr ot o c ol, t h e I  C  H   G ui d eli n e  E 6,  a n d  all 
a p pli c a bl e l o c al r e g ul at or y r e q ui r e  m e nts.   G  C P is  a n i nt er n ati o n al  et hi c al  a n d s ci e ntifi c  q u alit y 
st a n d ar d  us e d f or  d esi g ni n g,  c o n d u cti n g, r e c or di n g,  a n d r e p orti n g st u di es i n v ol vi n g t h e 
p arti ci p ati o n  of  h u  m a n s u bj e cts.   Al k er  m es is  c o  m  mitt e d t o  c o  m pl yi n g   wit h t his st a n d ar d t o 
pr o vi d e  ass ur a n c e t h at t h e ri g hts, s af et y,  a n d   w ell - b ei n g  of st u d y s u bj e cts   will  b e  pr ot e ct e d, 
c o nsist e nt   wit h t h e  pri n ci pl es  h a vi n g t h eir  ori gi n i n t h e   D e cl ar ati o n  of   H elsi n ki. 
1 7. 3.    
W ritt e n I nf o r  m e d   C o ns e nt   
T h e  I n v esti g at or ( or  a ut h ori z e d  d esi g n e e)  at  e a c h  c e nter   will  e ns ur e t h at t h e s u bj e ct  is  gi v e n f ull 
a n d  a d e q u at e  or al  a n d   writt e n i nf or  m ati o n  a b o ut t h e  n at ur e,  p ur p os e,  p ot e nti al  a n d  p ossi bl e ris ks 
a n d  b e n efits  of t h e st u d y.  E a c h  pr os p e cti v e s u bj e ct   will r e c ei v e  a n  I  R  B/IE  C - a p pr o v e d i nf or  m e d 
c o ns e nt f or  m (I C F) t h at s u  m  m ari z es t h e  p erti n e nt st u d y i nf or  m ati o n  a n d   will  b e  gi v e n  a  m pl e 
ti  m e t o r e a d t h e f or  m  a n d  as k  q u esti o ns  a b o ut t h e st u d y. All i nf or  m ati o n is t o  b e  pr o vi d e d i n  a 
l a n g u a g e  u n d erst a n d a bl e t o t h e s u bj e ct  a n d   m ust  n ot i n cl u d e  a n y l a n g u a g e t h at   w ai v es t h e 
s u bj e ct’s le g al ri g hts.  Pr os p e cti v e s u bj e cts   m ust  als o  b e i nf or  m e d  of t h eir ri g ht t o   wit h dr a  w 
c o ns e nt   wit h o ut  pr ej u di c e  at  a n y ti  m e  d uri n g t h e st u d y. If t h e s u bj e ct  c h o os es t o  p arti ci p at e, 
h e/s h e   m ust si g n t h e I  C F  b ef or e  a n y st u d y-s p e cifi c  pr o c e d ur es  ar e  c o n d u ct e d. 
A  ll s u bj e cts   will  b e i nf or  m e d  of t h eir ri g hts t o  pri v a c y  a n d   will  b e   m a d e  a  w ar e t h at t h e st u d y  d at a 
will  b e s u b  mitt e d t o   Al k er  m es, t h e   I  R  B/IE  C , t h e   C  R  O if  a p pli c a bl e, a n d t o r e g ul at or y  a ut h oriti es 
f or r e vi e  w  a n d  e v al u ati o n f or t h e  d ur ati o n  of t h e st u d y  a n d  u ntil t h e  pr oj e ct  h as  b e e n  a p pr o v e d 
f or   m ar k eti n g,  or is   wit h dr a  w n fr o  m i n v esti g ati o n.  T h e y   will  als o  b e i nf or  m e d t h at t h e st u d y 
m o nit or   m a y i ns p e ct t h eir   m e di c al r e c or ds t o  v erif y t h e  a c c ur a c y  a n d  c o  m pl et e n ess  of t h e st u d y 
r e c or ds  a n d r es ults. 
Si g nifi c a nt   c h a n g es t o t h e  pr ot o c ol  or  pr o d u ct s af et y i nf or  m ati o n   m a y r e q uir e  a r e visi o n  of t h e 
I  C F,   w hi c h   m ust  b e r e vi e  w e d  a n d  a p pr o v e d  b y t h e I R  B/IE  C ,  a n d t h e n si g n e d  b y  all  a p pli c a bl e 
st u d y  p arti ci p a nts. 




 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  5 7  of  6 7 
1 8.    
D  A  T  A   H  A  N  D  LI  N  G   A  N  D   R  E  C  O  R  D  K  E  E PI  N  G   
A n  o v er vi e  w  of st u d y  d at a  h a n dli n g  a n d r e c or d k e e pi n g  pr o c e d ur es  a n d r estri cti o ns is  pr o vi d e d i n 
t h e s u bs e q u e nt s e cti o ns;  pl e as e r ef er t o t h e   C S  A f or f urt h er  d et ails. 
1 8. 1.    
D at a   C a pt u r e   
As st at e d i n   S e cti o n  1 6. 1 , t his st u d y   will  us e  e  C  R Fs f or  c a pt uri n g  d at a.   All  e ntri es,  c orr e cti o ns, 
a n d  alt er ati o ns   will  b e   m a d e  b y t h e  I n v esti g at or  or  ot h er  a ut h ori z e d st u d y  p ers o n n el.   All  d at a 
e ntri es   will  b e  v erifi e d f or  a c c ur a c y  a n d  c orr e ct n ess   b y i n d e p e n d e nt   m o nit ors.  T h e  el e ctr o ni c 
d at a  c a pt ur e s yst e  m   m ai nt ai ns  a f ull  a u dit tr ail.  
All  el e ctr o ni c s o ur c e  d at a  c oll e ct e d  o utsi d e  of t h e  e  C  R F s u c h  as   e- di ari es,  c e ntr al l a b or at or y, 
c e ntr al  E  C  G,  or  c e ntr al   M  RI  d at a   will  b e tr a nsf err e d  dir e ctl y t o   Al k er  m es f or i n c or p or ati o n i nt o 
t h e fi n al  d at as ets. A  p a p er  c o p y  of  all l a b or at or y r e p orts   will r e  m ai n   wit h t h e s o ur c e  d o c u  m e nts 
at t h e st u d y sit e.   All  o ut  of r a n g e l a b or at or y  v al u es   will  b e  d e e  m e d  as  cli ni c all y si g nifi c a nt  or  n ot 
cli ni c all y si g nifi c a nt  b y t h e  I n v esti g at or.   Cli ni c all y si g nifi c a nt  v al u es   will  b e  c o nsi d er e d   A Es  a n d 
r e c or d e d  as s u c h  o n t h e  e  C  R Fs. 
A Es   will  b e  c o d e d  usi n g   M e d  D  R  A.   C o n c o  mit a nt   m e di c ati o ns   will  b e  c at e g ori z e d  usi n g t h e 
W  H  O  -A T  C  cl assifi c ati o n s yst e  m.   
1 8. 2.    
I ns p e cti o n  of   R e c o r ds  
Al k er  m es  or its r e pr es e nt ati v e   will  b e  all o  w e d t o  c o n d u ct sit e  visits t o t h e i n v esti g ati o n al 
f a ciliti es f or t h e  p ur p os e  of   m o nit ori n g  a n y  as p e ct  of t h e st u d y.  T h e I n v esti g at or a gr e es t o  all o  w 
t h e   m o nit or t o i ns p e ct t h e  dr u g st or a g e  ar e a, st u d y  dr u g st o c ks,  dr u g  a c c o u nt a bilit y r e c or ds, 
s u bj e ct  c h arts  a n d s o ur c e  d o c u  m e nts,  a n d  ot h er r e c or ds r el ati v e t o st u d y  c o n d u ct. 
1 8. 3.    
R et e nti o n  of   R e c o r ds   
R et e nti o n  a n d st or a g e  of  all  ess e nti al  cli ni c al st u d y  d o c u  m e nts s h all  b e  g o v er n e d  b y t h e t er  ms 
a n d  c o n diti o ns  of t h e sit e’s   C S  A  a n d i n  a c c or d a n c e   wit h I C  H  g ui d eli n es/l o c al r e g ul at or y 
r e q uir e  m e nts  as f oll o  ws: 
Ess e nti al  d o c u  m e nts s h o ul d  b e r et ai n e d  u ntil  at l e ast  2  y e ars  aft er t h e l ast  a p pr o v al  of  a 
m ar k eti n g  a p pli c ati o n i n  a n I C  H r e gi o n  a n d  u ntil t h er e  ar e  n o  p e n di n g  or  c o nt e  m pl at e d   m ar k eti n g 
a p pli c ati o ns i n  a n I C  H r e gi o n  or  at l e ast  2  y e ars  h a v e  el a ps e d si n c e t h e f or  m al  dis c o nti n u ati o n  of 
cli ni c al  d e v el o p  m e nt  of t h e i n v esti g ati o n al  pr o d u ct.  T h es e  d o c u  m e nts s h o ul d  b e r et ai n e d f or  a 
l o n g er  p eri o d,  h o  w e v er, if r e q uir e d  b y t h e  a p pli c a bl e r e g ul at or y r e q uir e  m e nts  or  b y t h e t er  ms  of 
t h e   C S  A. It is t h e r es p o nsi bilit y  of t h e s p o ns or t o i nf or  m t h e In v esti g at or/i nstit uti o n  as t o  w h e n 
t h es e  d o c u  m e nts  n o l o n g er  n e e d t o  b e r et ai n e d. 
S u bj e cts’   m e di c al fil es s h o ul d  b e r et ai n e d i n  a c c or d a n c e   wit h t h e  a p pli c a bl e l e gisl ati o n  a n d i n 
a c c or d a n c e   wit h t h e   m a xi  m u  m  p eri o d  of ti  m e  p er  mitt e d  b y t h e  h os pit al, i nstit uti o n,  or  pri v at e 
pr a cti c e ,   w hi ch e v er is l o n g er. 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  5 8  of  6 7 
1 8. 4.    
Us e  of I nf o r  m ati o n  a n d  P u bli c ati o n  P oli c y   
D at a  g e n er at e d i n t his st u d y  ar e  pr o pri et ar y i nf or  m ati o n t h at is t h e s ol e  pr o p ert y  of   Al k er  m es. 
R es ults  of t h e st u d y  ar e t o  b e  h el d i n  c o nfi d e n c e  b y  b ot h t h e I n v esti g at ors  a n d t h e s p o ns or. 
Pl e as e r ef er t o t h e   C S  A f or  d et ails  o n t h e  pr o c e d ur es f or  p u blis hi n g  a n d  pr es e nti n g  d at a. 




 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  6 0  of  6 7 
O'  G or  m a n, J.,   H.   K.   R uss ell, J.  Li,   G.  P hilli ps,   N.   C.   K ur u k ul as uri y a  a n d   V.   Vi gli ett a ( 2 0 1 5). 
" Eff e ct  of   As piri n  Pr etr e at  m e nt  or  Sl o  w   D os e  Titr ati o n  o n  Fl us hi n g  a n d   G astr oi nt esti n al  E v e nts 
i n   H e alt h y   V ol u nt e ers   R e c ei vi n g   D el a y e d-r el e as e   Di  m et h yl  F u  m ar at e. " Cli n.  T h er   3 7 ( 7):  1 4 0 2-
1 4 1 9. 
P hilli ps, J.  T.  a n d   R. J.  F o x ( 2 0 1 3).  "  B  G- 1 2 i n   m ulti pl e s cl er osis. "  S e  mi n   N e ur ol  3 3 ( 1):  5 6- 6 5. 
P hilli ps, J.  T.,   K.  S el  m aj,   R.   G ol d,   R. J.  F o x,  E.   H a vr d o v a,   G.   Gi o v a n n o ni,   H.   A b o urj ail y,   A. 
P a c e,   M.   N o v as,   C.   H ot er  m a ns,   V.   Vi gli ett a  a n d  L.   M elt z er ( 2 0 1 5).  "  Cli ni c al  Si g nif i c a n c e  of 
G astr oi nt esti n al  a n d  Fl us hi n g  E v e nts i n  P ati e nts   wit h   M ulti pl e  S cl er osis  Tr e at e d   wit h   D el a y e d  -
R el e as e   Di  m et h yl  F u  m ar at e. "   I nt J   M S   C ar e 1 7 ( 5):  2 3 6- 2 4 3. 
P ol  m a n,   C.   H.,  S.   C.   R ei n g ol d,   B.   B a n  w ell,   M.   Cl a n et, J.   A.   C o h e n,   M.  Fili p pi,   K.  F uji h ar a,  E. 
H a vr d o v a,   M.   H ut c hi ns o n,  L.   K a p p os,  F.   D.  L u bli n,   X.   M o nt al b a n,  P.   O'  C o n n or,   M.  S a n d b er g-
W oll h ei  m,   A. J.  T h o  m ps o n,  E.   W a u b a nt,   B.   W ei ns h e n k er  a n d J.  S.   W oli ns k y ( 2 0 1 1).  "  Di a g n osti c 
crit eri a f or   m ulti pl e s cl er osis:  2 0 1 0 r e visi o ns t o t h e   M c  D o n al d  crit eri a. "    A n n.   N e ur ol 6 9 ( 2):  2 9 2-
3 0 2. 
P os n er,   K.,   G.   K.   Br o  w n,   B.  St a nl e y,   D.   A.   Br e nt,   K.   V.   Y ers h o v a,   M.   A.   O q u e n d o,   G.   W. 
C urri er,   G.   A.   M el vi n,  L.   Gr e e n hill,  S.  S h e n  a n d J. J.   M a n n ( 2 0 1 1).  " T h e   C ol u  m bi a-  S ui ci d e 
S e v erit y   R ati n g  S c al e: i niti al  v ali dit y  a n d i nt er n al  c o nsist e n c y fi n di n gs fr o  m t hr e e   m ultisit e 
st u di es   wit h  a d ol es c e nts  a n d  a d ults. "  A  m J  Ps y c hi atr y   1 6 8 ( 1 2):  1 2 6 6- 1 2 7 7. 
R o p p er,   A.   H. ( 2 0 1 2).  " T h e  " p ois o n  c h air " tr e at  m e nt f or   m ulti pl e s cl er osis. "   N  E n gl J   M e d   
3 6 7 ( 1 2):  1 1 4 9- 1 1 5 0. 
T or n at or e,   C., J.  Li,  T.   M a,   C.  v o n   H e h n, J.   W als h  a n d J.  Z a  m br a n o ( 2 0 1 4).   Eff e ct  of   Bis  m ut h 
S u bs ali c yl at e  o n   G astr oi nt esti n al  E v e nts   Ass o ci at e d   wit h   D el a y e d -R el e as e   Di  m et h yl  F u  m ar at e: 
A   D o u bl e-  Bli n d,  Pl a c e b o-  C o ntr oll e d  St u d y.  2 0 1 4 J oi nt   A  C T  RI  M S- E  X T  RI  M S   M e eti n g,   B ost o n, 
M  A.   
Tr e  ml ett ,   H.,   Y.  Z h a o,  P.   Ri e c k  m a n n  a n d   M.   H ut c hi ns o n ( 2 0 1 0).  "  N e  w  p ers p e cti v es i n t h e 
n at ur al  hist or y  of   m ulti pl e s cl er osis. "  N e ur ol o g y   7 4 ( 2 4):  2 0 0 4- 2 0 1 5. 
W er d e n b er g,   D.,   R. J os hi,  S.   W olffr a  m,   H.  P.   M er kl e  a n d  P.  L a n g g ut h ( 2 0 0 3).  " Pr es yst e  mi c 
m et a b olis  m  a n d i nt esti n al  a bs or pti o n  of  a nti ps ori ati c f u  m ari c  a ci d  est ers. "   Bi o p h ar  m.   Dr u g 
Dis p os   2 4 ( 6):  2 5 9- 2 7 3. 
 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  6 1  of  6 7 
A P P  E  N  DI  X   A.     I  N  DI  VI  D  U  A  L   G  A S  T  R  OI  N  T  E S  TI  N  A  L  S  Y  M P  T  O  M   A  N  D 
I  M P  A  C  T  S  C  A  L  E (I  GI SI S ) 
T his  q u esti o n n air e  as ks  y o u  a b o ut  p ot e nti al  g astr oi nt esti n al s y  m pt o  ms  y o u   mi g ht f e el  aft er t a ki n g 
y o ur st u d y  dr u g.  F or  e a c h  of t h es e s y  m pt o  ms,  y o u   will i n di c at e   w h et h er  or  n ot  y o u  e x p eri e n c e d 
t h e s y  m pt o  m  a n d if  y o u  di d,  h o  w i nt e ns e t h e s y  m pt o  m   w as,  h o  w l o n g  aft er t a ki n g  y o ur st u d y 
dr u g t h at it st art e d,  h o  w l o n g it l ast e d,  a n d  h o  w   m u c h it  aff e ct e d  y o ur  d ail y lif e.  T h e 
g astr oi nt esti n al s y  m pt o  ms  y o u   will  b e  as k e d  a b o ut i n t his  q u esti o n n air e i n cl u d e  n a us e a, 
v o  miti n g,  a b d o  mi n al  p ai n ( b ot h  u p p er  a n d l o  w er i n l o c ati o n),  a n d  di arr h e a.   Y o u   m a y  e x p eri e n c e 
o n e  or   m or e  of t h es e s y  m pt o  ms  or  n o n e  at  all. 
 
Y o u s h o ul d  c o  m pl et e t his  q u esti o n n air e   wit hi n  9  h o urs  aft er t a ki n g  y o ur st u d y  dr u g.   As  y o u   will 
b e t a ki n g  y o ur st u d y  dr u g t  wi c e  a  d a y,  y o u  will  b e  c o  m pl eti n g t his  q u esti o n n air e   t  wi c e a  d a y  as 
w ell.   All  q u esti o ns i n t his  q u esti o n n air e r ef er t o t h e  p eri o d  of   ti  m e si n c e  y o u l ast  c o  m pl et e d t his 
q u esti o n n ai r e    wit h t h e  e x c e pti o n  of   w h e n  y o u  c o  m pl et e t his  q u esti o n n air e f or t h e first ti  m e. 
W h e n  y o u first  c o  m pl et e t his  q u esti o n n air e, t h e  p eri o d  of ti  m e is   si n c e  y o u r fi rst  d os e.  
 
1.  H o  w i nt e ns e  h as  y o ur   N  A  U S  E  A   b e e n  o n  a s c al e (s h o  w n  b el o  w)  fr o  m  0 (di d  n ot  h a v e) t o  1 0 
( e xtr e  m e) ? 
 
 
a.  W h e n  di d  y o ur  n a us e a st art ? _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
b.  W h e n  di d  y o ur  n a us e a st o p ? _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
c.  H o  w   m u c h  h as  y o ur  n a us e a I  N T E  R F E  R E  D   wit h  y o ur  a bilit y t o  a c c o  m plis h 
y o ur r e g ul ar  d ail y  a cti viti es ? ( c h o os e  o n e):  
 
R e g ul ar  d ail y  a cti viti es r ef er t o t h e t hi n gs  y o u  us u all y  d o, s u c h  as 
s h o p pi n g,  h o us e h ol d   w or k, t a ki n g  c ar e  of  a  c hil d  or f a  mil y   m e  m b er, 
e x er cisi n g,  et c.  
 
i.   N ot  at  all   
ii.   Sli g htl y  
iii.   M o d er at el y   
i v.   Q uit e  a  bit   
v.    E xtr e  m el y  


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  6 2  of  6 7 
2.    H o  w i nt e ns e  h as  y o ur   V  O  MI  T I  N  G    b e e n  o n  a s c al e (s h o  w n  b el o  w) fr o  m  0 ( di d  n ot  h a v e) t o 
1 0 ( e xtr e  m e) ?  
 
 
a.  W h e n  di d  y o ur  v o  miti n g st art ? _ _ _ _ _ _ _ _ _ _ _ _ _ _  
b.  W h e n  di d  y o ur  v o  miti n g st o p ? _ _ _ _ _ _ _ _ _ _ _ _ _ _  
c.  H o  w   m u c h  h as  y o ur  v o  miti n g I  N T E  R F E  R E  D   wit h  y o ur  a bilit y t o 
a c c o  m plis h  y o ur r e g ul ar  d ail y  a cti viti es ? ( c h o os e  o n e):  
 
R e g ul ar  d ail y  a cti viti es r ef er t o t h e t hi n gs  y o u  us u all y  d o, s u c h  as 
s h o p pi n g,  h o us e h ol d   w or k, t a ki n g  c ar e  of  a  c hil d  or f a  mil y   m e  m b er, 
e x er cisi n g,  et c.  
 
i.   N ot  at  all   
ii.   Sli g htl y  
iii.   M o d er at el y   
i v.   Q uit e  a  bit   
v.    E xtr e  m el y  
 
 
3.    H o  w i nt e ns e  h as  y o ur   U P P  E  R   A  B  D  O  MI  N  A  L  P  A  I  N  b e e n  o n  a s c al e (s h o  w n  b el o  w) fr o  m  0 
( di d  n ot  h a v e) t o  1 0 ( e xtr e  m e) ? 
 
 
a.  W h e n  di d  y o ur  u p p er  a b d o  mi n al  p ai n st art ? _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
b.  W h e n  di d  y o ur  u p p er  a b d o  mi n al  p ai n st o p ? _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
c.  H o  w   m u c h  h as  y o ur  u p p er  a b d o  mi n al  p ai n I  N T E  R F E  R E  D   wit h  y o ur 
a bilit y  t o  a c c o  m plis h  y o ur r e g ul ar  d ail y  a cti viti es ? ( c h o os e  o n e): 
 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  6 3  of  6 7 
R e g ul ar  d ail y  a cti viti es r ef er t o t h e t hi n gs  y o u  us u all y  d o, s u c h  as 
s h o p pi n g,  h o us e h ol d   w or k, t a ki n g  c ar e  of  a  c hil d  or f a  mil y   m e  m b er, 
e x er cisi n g,  et c.  
 
i.   N ot  at  all   
ii.   Sli g htl y  
iii.   M o d er at el y   
i v.   Q uit e  a  bit   
v.    E xtr e  m el y  
 
 
4.    H o  w i nt e ns e  h as  y o ur   L  O  W  E  R   A  B  D  O  MI  N  A  L  P  AI  N    b e e n  o n  a s c al e (s h o  w n  b el o  w) fr o  m 
0 ( di d  n ot  h a v e) t o  1 0 ( e xtr e  m e) ? 
 
 
a.  W h e n  di d  y o ur l o  w er  a b d o  mi n al  p ai n st art ?   _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
b.  W h e n  di d  y o ur l o  w er  a b d o  mi n al  p ai n st o p ? _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
c.  H o  w   m u c h  h as  y o u  r l o  w er  a b d o  mi n al  p ai n I  N T E  R F E  R E  D   wit h  y o ur 
a bilit y t o  a c c o  m plis h  y o ur r e g ul ar  d ail y  a cti viti es ? ( c h o os e  o n e):  
 
R e g ul ar  d ail y  a cti viti es r ef er t o t h e t hi n gs  y o u  us u all y  d o, s u c h  as 
s h o p pi n g,  h o us e h ol d   w or k, t a ki n g  c ar e  of  a  c hil d  or f a  mil y   m e  m b er, 
e x er cisi n g,  et c.  
 
i.   N ot  at  all   
ii.   Sli g htl y  
iii.   M o d er at el y   
i v.   Q uit e  a  bit   
v.    E xtr e  m el y  
 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  6 4  of  6 7 
5.    H o  w i nt e ns e  h as  y o ur   DI  A  R  R  H  E  A   b e e n  o n  a s c al e (s h o  w n  b el o  w) fr o  m  0 ( di d  n ot  h a v e) t o 
1 0 ( e xtr e  m e) ?  
 
 
a.  W h e n   di d  y o ur  di arr h e a  st art ? _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
b.  W h e n  di d  y o ur  di arr h e a   st o p ? _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
c.  H  o  w   m u c h  h as  y o ur  di arr h e a I  N T E  R F E  R E  D   wit h  y o ur  a bilit y t o 
a c c o  m plis h  y o ur r e g ul ar  d ail y  a cti viti es ? ( c h o os e  o n e):  
 
R e g ul ar  d ail y  a cti viti es r ef er t o t h e t hi n gs  y o u  us u all y  d o, s u c h  as 
s h o p pi n g,  h o us e h ol d   w or k, t a ki n g  c ar e  of  a  c hil d  or f a  mil y   m e  m b er, 
e x er c isi n g,  et c. 
 
i.   N ot  at  all   
ii.   Sli g htl y  
iii.   M o d er at el y   
i v.   Q uit e  a  bit   
v.    E xtr e  m el y  


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  6 5  of  6 7 
A P P  E  N  DI  X     B.   G  L  O  B  A  L   G  A S  T  R  OI  N  T  E S  TI  N  A  L  S  Y  M P  T  O  M   A  N  D 
I  M P  A  C  T  S  C  A  L  E (  G  GI SI S )  
T his  q u esti o n n air e  as ks  y o u  a b o ut t h e  o v er all  e x p eri e n c e  of  g astr oi nt esti n al s y  m pt o  ms  y o u   mi g ht 
f e el  aft er t a ki n g  y o ur st u d y  dr u g. T h e  g astr oi nt esti n al s y  m pt o  ms t o t hi n k  a b o ut  ar e  n a us e a, 
v o  miti n g,  a b d o  mi n al  p ai n ( b ot h  u p p er  a n d l o  w er i n l o c ati o n),  a n d  di arr h e a.   Y o u   m a y  e x p eri e n c e 
o n e  or   m or e  of t h es e s y  m pt o  ms  or  n o n e  at  all. 
 
Y o u s h o ul d  c o  m pl et e t his  q u esti o n n air e i n t h e   m or ni n g  b ef or e  y o u t a k e  y o ur st u d y   m e di c ati o n. 
Y o u   will  o nl y  c o  m pl et e t his  q u esti o n n air e   o n c e   p er  d a y.   All  q u esti o ns i n t his  q u esti o n n air e r ef er 
t o  y o ur  e x p eri e n c e o v e r t h e  p ast  2 4  h o u rs . 
 
1.   R at e t h e  i nt e nsit y of  y o ur  GI   s y  m pt o  ms i n  g e n e r al o v er t h e  p ast  2 4  h o urs o n  a s c al e 
fr o  m  0 ( di d  n ot  h a v e) t o  1 0 ( e xtr e  m e)  as s h o  w n  b el o  w. 
 
 
 
 
2.   R at e  h o  w b ot h e rs o  m e  y o ur   GI   s y  m pt o  ms h a v e  b e e n i n  g e n er al  o v er t h e  p ast  2 4  h o urs  
o n  a s c al e fr o  m  0 ( di d  n ot  h a v e) t o  1 0 ( e xtr e  m e)  as s h o  w n  b el o  w.   
 
 
 
 


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  6 6  of  6 7 
3.   H o  w   m u c h  h a v e  y o ur   GI s y  m pt o  ms i nt e rf e r e d wit h  y o ur  a bilit y t o  a c c o  m plis h 
y o ur r e g ul ar  d ail y  a cti viti es  o v er t h e  p ast  2 4  h o urs ? ( c h o os e  o n e):  
 
R e g ul ar  d ail y  a cti viti es r ef er t o t h e t hi n gs  y o u  us u all y  d o, s u c h  as s h o p pi n g, 
h o us e h ol d   w or k, t a ki n g  c ar e  of  a  c hil d  or f a  mil y   m e  m b er,  e x er cisi n g ,  et c.  
 
 
a.    
N ot  at  all   
b.    
Sli g htl y  
c.    
M o d er at el y   
d.    
Q uit e  a  bit   
e.    
E xtr e  m el y  
 
 
 
4.  Ar e  y o u  c urr e ntl y  e  m pl o y  e d (  w or ki n g f or  p a y) ?  
 
If   N  O,  c h e c k  "  N  O "  b el o  w  a n d  y o u  h a v e  c o  m pl et e d t his  q u esti o n n air e. 
If  Y E S,  c h e c k  “ Y E S ”  b el o  w  a n d  pl e as e  a ns  w er  q u esti o ns  5  a n d  6. 
 
_ _ _  N  O 
_ _ _  Y E S 
 
5.  D uri n g t h e  p ast  2 4  h o urs,  h o  w   m a n y  h o urs  of   w or k  di d  y o u   miss  b e c a us e  of  y o ur   GI 
s y  m pt o  ms ?  
 
H o  w   m a n y  h o urs t h at  y o u   w er e s u p p os e d t o   w or k  or   w er e s c h e d ul e d t o   w or k  di d  y o u 
miss  b e c a us e  of  y o ur   GI s y  m pt o  ms ? If  y o u  di d n’t   miss  a n y   w or k, i n di c at e  “ 0 ”  h o urs 
b el o  w.   D o  n ot i n cl u d e ti  m e  y o u   miss e d t o  p arti ci p at e i n t his st u d y.  
If  y o u   w er e n’t s c h e d ul e d t o   w or k  d uri n g t h e  p ast  2 4  h o urs,  c h e c k  “  N ot  a p pli c a bl e ” 
b el o  w.  
 
 
_ _ _  H  O  U  R S   
_ _ _  N ot  a p pli c a bl e 
 
6.  H o  w   m u c h  h a v e  y o ur   GI s y  m pt o  ms  aff e ct e d  y o ur  pr o d u cti vit y   w hil e  y o u   w er e   w or ki n g 
o v er t h e  p ast  2 4  h o urs ? ( c h o os e  o n e)  
 
W as t h er e ti  m e  d uri n g t h e  p ast  2 4  h o urs   w h e n  y o u   w er e li  mit e d i n t h e  a  m o u nt  or  ki n d 
of   w or k  y o u  c o ul d  d o  or  y o u  a c c o  m plis h e d l ess t h a n  y o u  us u all y  d o  b e c a us e  of  y o ur 
GI s y  m pt o  ms ?   


 
 
Al k er  m es, I n c.   
Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v  2. 0 (  A  m e n d  m e nt  1. 0) 
C  O  N FI  D E  N TI  A L   
P a g e  6 7  of  6 7 
a.    N ot  at  all   
b.   Sli g ht l y 
c.    M o d er at el y   
d.   Q uit e  a  bit   
e.    E xtr e  m el y  

SAP_001.pdf: 
S T A TI S TI C A L  A N A LY SI S  P L A N 
A L K 8 7 0 0- A 3 0 2 / N C T 0 3 0 9 3 3 2 4
St u d y  Titl e:    
A  P h as e  3  St u d y i n  S u bj e cts   wit h   R el a psi n g   R e  mitti n g   M ulti pl e  S cl er osis 
t o  E v al u at e t h e  T ol er a bilit y  of   A L  K S  8 7 0 0  a n d   Di  m et h yl F u  m ar at e  
D o c u  m e nt  St at us:     
Fi n al    V ersi o n  1. 0 
D o c u  m e nt   D at e:     
F e br u ar y   2 0,  2 0 1 9 
B as e d  o n:     
Al k er  m es   A L  K 8 7 0 0-  A 3 0 2 st u d y  pr ot o c ol 
G er  m a n y  -s p e cifi c   A  m e n d  m e nt  2. 2 (i n c or p or at e d   A d  mi nistr ati v e   C h a n g e 
M e  m o  2):  1 4   D e c  2 0 1 8 
A  m e n d  m e nt  2. 0 (i n c or p or at e d   A d  mi nistr ati v e   C h a n g e   M e  m o  1):  2 0  S e p 
2 0 1 8 
v  2. 1 (i n c or p or at es  P ol a n d-s p e cifi c   A  m e n d  m e nt  1. 1):  2 3   A u g  2 0 1 7 
A  m e n d  m e nt  1. 0:  1 5   D e c  2 0 1 6   
S p o ns or:    
Al k er  m es, I n c.   
8 5 2   Wi nt er  Str e et 
W alt h a  m,   M  A   0 2 4 5 1 
U S  A   
C  O  N FI  D  E  N  TI  A  L   
Inf or  m ati o n  a n d  d at a i n t his  d o c u  m e nt  c o nt ai n tr a d e s e cr ets  a n d  pri vil e g e d  or  c o nfi d e nti al i nf or  m ati o n, 
w hi c h is t h e  pr o p ert y  of   Al k er  m es, I n c.   N o  p ers o n is  a ut h ori z e d t o   m a k e it  p u bli c   wit h o ut t h e   writt e n 
p er  missi o n  of   Al k er  m es, I n c.  T h es e r estri cti o ns  or  dis cl os ur es   will  a p pl y  e q u al l y t o  all f ut ur e i nf or  m ati o n 
s u p pli e d t o  y o u t h at is i n di c at e d  as  pri vil e g e d  or  c o nfi d e nti al.  T his st u d y is  b ei n g  c o n d u ct e d i n 
c o  m pli a n c e   wit h  g o o d  cli ni c al  pr a cti c e, i n cl u di n g t h e  ar c hi vi n g  of  ess e nti al  d o c u  m e nts. 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2  of  3 7  
 
T  A  B  L  E   O F   C  O  N  T  E  N  T S   
A  B  B  R E  VI  A TI  O  N S   ......................................................................................................................... 4 
1.  
I  N T  R  O  D  U  C TI  O  N ........................................................................................................ 6 
1. 1.  
St u d y   O bj e cti v es  ........................................................................................................... 6 
1. 2.  
S u  m  m ar y  of t h e  St u d y   D esi g n  ...................................................................................... 7 
 
8  
 
8  
2.  
S  A  M P L E  SI Z E   A  N  D  S T  A TI S TI C  A L  P  O  W E  R   C  O  N SI  D E  R  A TI  O  N  ....................... 1 2 
3.  
D  A T  A   A  N  A L  Y SI S   .................................................................................................... 1 3 
3. 1.  
G e n er al  St atisti c al   M et h o d ol o g y   ................................................................................ 1 3 
3. 2.  
St u d y  P o p ul ati o ns  ....................................................................................................... 1 3 
3. 2. 1.  
D efi niti o ns  of   A n al ysis  P o p ul ati o ns (  A n al ysis  S ets)  .................................................. 1 3 
3. 2. 2.  
Dis p ositi o n   .................................................................................................................. 1 4 
3. 2. 3.  
Pr ot o c ol   D e vi ati o ns  .................................................................................................... 1 4 
3. 3.  
D e  m o gr a p hi cs  a n d   B as eli n e   C h ar a ct eristi cs   ............................................................... 1 4 
3. 4.  
Pri or  a n d   C o n c o  mit a nt   M e di c ati o ns  ........................................................................... 1 5 
3. 5.  
Tr e at  m e nt   A d h er e n c e   R at e  a n d  E xt e nt  of  E x p os ur e  ................................................... 1 5 
3. 6.  
GI  T ol er a bilit y  a n d  Effi c a c y   A n al ys es   ....................................................................... 1 6 
3. 6. 1.  
G e n er al   C o nsi d er ati o ns  ............................................................................................... 1 6 
3. 6. 2.  
GI  T ol er a bilit y   Ass ess  m e nt   ........................................................................................ 1 6 
3. 6. 3.  
Ot h er  E x pl or at or y  E n d p oi nts  ...................................................................................... 1 9 
3. 7.  
S af et y   A n al ys es ( P art   A  a n d  P art   B) ........................................................................... 2 1 
3. 7. 1.  
A d v ers e  E v e nts   ........................................................................................................... 2 2 
3. 7. 2.  
D e at hs,  S eri o us  a n d   Ot h er  Si g nifi c a nt   A d v ers e  E v e nts  .............................................. 2 3 
3. 7. 3.  
A d v ers e  E v e nts  of  S p e ci al I nt er est   ............................................................................. 2 3 
3. 7. 4.  
Cli ni c al  L a b or at or y  P ar a  m et ers   .................................................................................. 2 4 
3. 7. 5.  
Vit al  Si g ns  a n d  E  C  G   ................................................................................................... 2 7 
3. 7. 6.  
C ol u  m bi a  S ui ci d e  S e v erit y   R ati n g  S c al e (  C  -S S  R S)  ................................................... 2 8 
4.  
I  N T E  RI  M   A  N  A L  Y S E S   A  N  D D  A T  A   M  O  NI T  O  RI  N  G   C  O  M  M  I T T E E 
(  D  M  C) ......................................................................................................................... 2 9 
5.  
C  H  A  N  G E S I  N   C  O  N  D  U  C T   O  R  P L  A  N  N E  D   A  N  A L  Y S E S  F  R  O  M  T  H E 
P  R  O T  O  C  O L  ............................................................................................................... 3 0 
6.  
D E FI  NI TI  O  N S   A  N  D   C  O  N  V E  N TI  O  N S  F  O  R   H  A  N  D LI  N  G   O F  T  H E   D  A T  A   .......... 3 1 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3  of  3 7  
 
6. 1.  
A n al ysis   Visit   Wi n d o  ws   ............................................................................................. 3 1 
6. 2.  
H a n dli n g  of  P arti al   D at es  of   C o n c o  mit a nt   M e di c ati o n   .............................................. 3 1 
6. 3.  
S af et y   D at a   H a n dli n g  .................................................................................................. 3 1 
7.  
G E  N E  R  A L  S T  A TI S TI  C  A L   M E T  H  O  D  O L  O  G  Y   ....................................................... 3 2 
7. 1.  
R e p orti n g  Pr e cisi o n   .................................................................................................... 3 2 
8.  
P  R  O  G  R  A  M  MI  N  G  S P E  CI FI  C  A TI  O  N S  ..................................................................... 3 3 
9.  
M  O  C  K  T  A  B L E S,  LI S TI  N  G S   A  N  D   G  R  A P  H S ( T L  G S)   ............................................ 3 4 
1 0.  
R E F E  R E  N  C E S   ........................................................................................................... 3 5 
A P P E  N  DI  X I   A L  K 8 7 0 0  -A 3 0 2  P  A  R T   A  S  A P   .............................................................................. 3 6 
A P P E  N  DI  X II   A E SI  S E  A  R  C  H   C  RI T E  RI  A   .................................................................................. 3 7 
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  4  of  3 7  
 
A  B  B  R  E  VI  A  TI  O  N S   
T h e f oll o  wi n g  a b br e vi ati o ns  ar e  us e d i n t h e st atisti c al  a n al ysis  pl a n. 
A b b r e vi ati o n  o r   T e r  m     
E x pl a n ati o n  o r   D efi niti o n   
A E   
A d v ers e  E v e nt   
A E SI   
A d v ers e  E v e nts  of  S p e ci al I nt er est   
A L  K  - P 
Al k ali n e  P h os p h at as e   
A L T   
Al a ni n e   A  mi n otr a nsf er as e   
A  N  C  O  V  A   
A n al ysis   Of   C o v  ari a n c e   
A S T   
As p art at e   A  mi n otr a nsf er as e   
A T  C   
A n at o  mi c al  T h er a p e uti c   C h e  mi c al [  Cl assifi c ati o n  S yst e  m]   
BI  D   
Bis I n   Di e [ T  wi c e   A   D a y]   
B  MI   
B o d y   M ass I n d e x   
B  U  N   
Bl o o d   Ur e a   Nitr o g e n 
CI   
C o nfi d e n c e I nt er v al 
C- S S  R S  
C ol u  m bi a  S ui ci d e  S e v erit y   R ati n g  S c al e   
D  M  C   
D at a   M o nit ori n g   C o  m  mitt e e   
D  M F   
Di  m et h yl   fu  m ar at e  ( T e cfi d er a® ) 
D  M T   
Dis e as e   M o dif yi n g  Tr e at  m e nt   
E  C  G  
El e ctr o c ar di o gr a  m  
e  C  R F  
El e ctr o ni c   C as e   R e p ort  F or  m  
 
 
 
 
 
  
E T  
E arl y  T er  mi n ati o n  
F  A S  
F ull   A n al ysis  S et   
F S  
F u n cti o n al  S yst e  m 
G d E   
G a d oli ni u  m- E n h a n ci n g 
G  GI SI S   
Gl o b al   G astr oi nt esti n al  S y  m pt o  m   A n d I  m p a ct  S c al e   
GI   
G astr oi nt esti n al   
H  D L   
Hi g h   D e nsit y  Li p o pr ot ei n   
I  GI SI S 
I n di vi d u al   G astr oi nt esti n al  S y  m pt o  m   A n d I  m p a ct  S c al e 
L  D  H  
L a cti c   D e h y dr o g e n as e  


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  5  of  3 7  
 
A b b r e vi ati o n  o r   T e r  m     
E x pl a n ati o n  o r   D efi niti o n   
L  D L  
L o  w   D e nsit y  Li p o pr ot ei n 
L L  N  
L o  w er  Li  mit   Of   N or  m al   R a n g e  
M e d  D  R  A   
M e di c al   Di cti o n ar y  F or   R e g ul at or y   A cti viti es   
M  M F   
M o n o  m et h yl  F u  m ar at e 
M  RI   
M a g n eti c   R es o n a n c e I  m a gi n g   
M S   
M ulti pl e  S cl er osis   
N  CI  -C T  C  A E    
N ati o n al   C a n c er I nstit ut e   C o  m  m o n  T er  mi n ol o g y   Crit eri a  F or   A d v ers e 
E v e nts   
P  C S  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt  
P  D E  A E  
P ost - dis c o nti n u ati o n E  m er g e nt   A d v ers e  E v e nt  
 
 
P T  
Pr ef err e d  T er  m  
Q  O L   
Q u alit y   Of  Lif e   
Q T c  B   
Q T   I nt er v al   C orr e ct e d   Usi n g   B a z ett’s F or  m ul a  
Q T c F   
Q T   I nt er v al   C orr e ct e d   Usi n g Fri d eri ci a’s   F or  m ul a 
R  R  M S   
R el a psi n g-  R e  mitti n g   M ulti pl e  S cl er osis   
S  A E  
S eri o us   A d v ers e  E v e nt  
S  D  
St a n d ar d   D e vi ati o n 
 
 
 
  
 
  
S  O  C  
S yst e  m   Or g a n   Cl ass   
 
 
T E  A E  
Tr e at  m e nt -E  m er g e nt   A d v ers e  E v e nt  
U L  N   
U p p er  Li  mit   Of   N or  m al   R a n g e   
W  B  C   
W hit e   Bl o o d   C ells 
W  H  O   
W orl d   H e alt h   Or g a ni z ati o n 
 
 
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  6  of  3 7  
 
1.    
I  N  T  R  O  D  U  C  TI  O  N 
T his st atisti c al  a n al ysis  pl a n ( S  A P)  d es cri b es t h e st atisti c al   m et h o ds  a n d  d at a  pr es e nt ati o n  s t o  b e 
us e d f or  a n al y zi n g  a n d r e p orti n g  effi c a c y  a n d s af et y  d at a f or st u d y   A L  K 8 7 0 0-  A 3 0 2.  T his st u d y 
e v al u ati n g t h e   GI t ol er a bilit y  of   A L  K S   8 7 0 0  a n d   D  M F   w as  c o  m p os e d  of t  w o  p arts,  P arts   A  a n d 
B.   B ot h  P arts   A  a n d   B   w er e i d e nti c al i n st u d y  d esi g n  a n d i n cl u d e d  a  5-  w e e k,  d o u bl e- bli n d 
tr e at  m e nt  p eri o d   wit h  2  bli n d e d tr e at  m e nt  ar  ms (  A L  KS  8 7 0 0  a n d   D  M F).  P art   A   w as  e x pl or at or y . 
P art   A  e v al u at e d t h e  utilit y  of  2  g astr oi nt esti n al (  GI) s y  m pt o  m s c al es (I n di vi d u al   GI  S y  m pt o  m 
a n d I  m p a ct  S c al e [I  GI SI S]  a n d   Gl o b al   GI  S y  m pt o  m  a n d I  m p a ct  S c al e [  G  GI SI S])  a n d  e n d p oi nts 
d eri v e d fr o  m t h e s c al es i n  ass es si n g   GI t ol er a bilit y i n  a d ult s u bj e cts   wit h r el a psi n g -r e  mitti n g 
m ulti pl e s cl er osis (  R  R  M S)  aft er  a d  mi nistr ati o n  of   A L  K S  8 7 0 0  or  di  m et h yl f u  m ar at e (  D  M F).    
P art   A  als o  e v al u at e d t h e s af et y  a n d t ol er a bilit y  of   A L  K S  8 7 0 0 i n  a d ult s u bj e cts   wit h   R  R  M S.   
A t ot al  o  f  1 2 0 s u bj e cts   w er e r a n d o  mi z e d t o tr e at  m e nt  i n  P art   A  of t h e st u d y.   A s e p ar at e S  A P  a n d 
Cli ni c al  St u d y   R e p ort (  C S  R) f or  P art   A st u d y   w er e fi n ali z e d  , w hil e  P art   B  of t h e st u d y   w as 
o n g oi n g  as  pl a n n e d.   
T h e  pri  m ar y, s e c o n d ar y  a n d  e x pl or at or y  e n d p oi nts f or t h e st u d y   w er e r e vis e d  b as e d  o n 
e x pl or at or y  a n al ys es  of t h e r es ults fr o  m  P art   A.   M aj or  c h a n g es t o t h e  pr ot o c ol i n cl u d e d: 
•    C h a n g e i n  pri  m ar y, s e c o n d ar y,  a n d  e x pl or at or y  e n d p oi nts  
•    C h a n g e i n t h e  a n al ysis  of  pri  m ar y, s e c o n d ar y,  a n d  e x pl or at or y  e n d p oi nts  
•    C h a n g e i n t h e  a n al ysis  of t h e s af et y  d at a    
•    I n cr e as e i n  n u  m b er  of s u bj e cts i n  P art   B  a n d f or t h e st u d y  
T his  d o c u  m e nt  h as  b e e n  pr e p ar e d  b as e d  o n  Pr ot o c ol   A L  K 8 7 0 0-  A 3 0 2  v 2. 0   (  Am e n d  m e nt  1. 0) 
( d at e d  1 5   D e c  2 0 1 6) [ 1],  v  2. 1 (i n c or p or at es  P olis h-s p e cifi c   A  m e n d  m e nt  1. 1) ( d at e d  2 3   A u g 
2 0 1 7)  [ 2],   A  m e n d  m e nt  2. 0 (i n c or p or at e d   A d  mi nistr ati v e   C h a n g e   M e  m o  1) ( d at e d  2 0  S e p  2 0 1 8) 
[ 3] a n d  G er  m a n y  -s p e cifi c   A  m e n d  m e nt  2. 2 (i n c or p or at e d   A d  mi nistr ati v e   C h a n g e   M e  m o  2) ( d at e d 
1 4   D e c  2 0 1 8 ) [ 4]. 
1. 1.    
St u d y  O  bj e cti v es  
T h e  o bj e cti v es  of  t his st u d y ar e  t o:  
•    E v al u at e t h e  utilit y  of t  w o  g astr oi nt esti n al ( GI  ) s y  m pt o  m s c al es (In di vi d u al   GI 
S y  m pt o  m  a n d I nt e nsit y  S c al e [I GI SI S  ]  a n d   Gl o b al   GI S y  m pt o  m  a n d I nt e nsit y  S c al e 
[G  GI SI S  ])  a n d  e n d p oi nts  d eri v e d fr o  m t h e s c al es i n  ass essi n g   GI t ol er a bilit y i n  a d ult 
s ubj e cts   wit h r el a psi n g r e  mitti n g   m ulti pl e s cl er osis (  R  R  M S)  aft er  a d  mi nistr ati o n  of 
A L  K S  8 7 0 0  or   di  m et h yl f u  m ar at e ( D  M F  ) i n  P art   A 
•    C o  m p ar e t h e   GI t ol er a bilit y  of   A L  K S  8 7 0 0  a n d   D  M F i n  a d ult s u bj e cts   wit h   R  R  M S 
usi n g t  w o   GI s y  m pt o  m s c al es (I  GI SI S  a n d   G  GI SI S)   wit h  e n d p oi nts i nf or  m e d fr o  m 
P art    A 
•    E v al u at e t h e s af et y  a n d t ol er a bilit y  of   A L  K S  8 7 0 0 i n  a d ult s u bj e cts   wit h   R  R  M S i n 
P arts   A  a n d   B  


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  7  of  3 7  
 
P art   A   C S  R  pr es e nt e d t h e r es ults  of  e v al u ati o n  of  utilit y  of t  w o  GI  S y  m pt o  ms s c al es, I  GI  GI S  a n d 
G  GI SI S    a n d  e n d p oi nts  d eri v e d fr o  m t h es e s c al es i n  ass essi n g   GI t ol er a bilit y i n  a d ult s u bj e cts 
wit h r el a psi n g r e  mitti n g   m ulti pl e s cl er osis (  R  R  M S)  aft er  a d  mi nistr ati o n  of   A L  K S  8 7 0 0  or 
di  m et h yl f u  m ar at e (  D  M F)  i n  P art   A.   
I n t his st u d y,   GI t ol er a bilit y  of   A L  K S  8 7 0 0  a n d   D  M F i n  a d ult s u bj e cts   wit h   R  R  M S will  b e 
c o  m p ar e d   wit h r e vis e d  e n d p oi nt s a n d s af et y  a n d t ol er a bilit y  of   A L  K S  8 7 0 0   will  b e  e v al u at e d 
b as e d  o n  p o ol e d  d at a fr o  m  P art   A   a n d   B.     
1. 2.    
S u  m  m a r y  of t h e  St u d y   D esi g n  
T his is  a r a n d o  mi z e d,  d o u bl e- bli n d,   m ulti c e nt er st u d y  t o  e v al u at e t h e t ol er a bilit y  of   A L  K S  8 7 0 0 
a n d  D  M F   i n  a d ult s u bj e cts   wit h   R  R  M S.  T h e st u d y   w as  c o n d u ct e d i n t  w o  p arts ( P arts   A  a n d   B). 
T h e st u d y  d esi g n is  a n  a d a pti v e  a p pr o a c h   w h er e  d at a fr o  m  P art   A   w as   us e d  t o   m o dif y t h e   GI 
t ol er a bilit y  e n d p oi nt(s) i n t h e st u d y.   
B ot h  P arts   A  a n d   B  ar e i d e nti c al i n st u d y  d esi g n  a n d i n cl u d e  a  5-  w e e k,  d o u bl e-  bli n d tr e at  m e nt 
p eri o d   wit h t  w o  bli n d e d tr e at  m e nt  ar  ms (  A L  K S  8 7 0 0  a n d   D  M F).  P art   A is  e x pl or at or y.  T h e first 
1 2 0  eli gi bl e s u bj e cts   will  b e r a n d o  mi z e d t o  o n e  of t h e t  w o tr e at  m e nt  gr o u ps i n  P art   A ( n = 6 0  p er 
gr o u p).   O n c e t h e r a n d o  mi z ati o n f or  P art   A is  c o  m pl et e, t h e  n e xt  3 8 0  eli gi bl e s u bj e cts   will  b e 
r a n d o  mi z e d i nt o  o n e  of t h e t  w o tr e at  m e nt  gr o u ps i n  P art   B ( n = 1 9 0  p er  gr o u p).   A c c or di n gl y, 
s u bj e cts  1- 1 2 0   will  b e r a n d o  mi z e d i nt o  P art   A  a n d s u bj e cts  1 2 1- 5 0 0   will  b e r a n d o  mi z e d i nt o  P art 
B.  S u bj e cts r a n d o  mi z e d i n  P art   A   will  n ot  b e  eli gi bl e t o  p arti ci p at e i n  P art   B.   
F oll o  wi n g  c o  m pl eti o n  of  P art   A, t h e s p o ns or  c o n d u ct e d  a  pl a n n e d,  u n bli n d e d  a n al ysis  of t h e 
P art  A   GI t ol er a bilit y  a n  d s af et y  d at a.  P art   B   will  b e  o n g oi n g  d uri n g t h e  a n al ysis  of t h e  P art   A 
d at a.   D at a fr o  m  P art   A  c a n  b e  us e d t o   m o dif y t h e  P art   B   GI t ol er a bilit y  e n d p oi nt(s).  P o ol e d   GI 
t ol er a bilit y  d at a fr o  m  P art   A  a n d  P art   B   will  b e  a n al y z e d f or t h e  pri  m ar y  a n d s e c o n d ar y 
e n d p oi nts. 
All st u d y  visits i n  P arts   A  a n d   B   will  b e  c o  m pl et e d  o n  a n  o ut p ati e nt  b asis.  T h e s cr e e ni n g  p eri o d 
is  u p t o  4   w e e ks ( 2 8  d a ys) i n cl u di n g  a  1-w e e k l e a d  -i n  p eri o d ( pri or t o r a n d o  mi z ati o n)  d uri n g 
w hi c h s u bj e cts   will  c o  m pl et e t  w o s elf  -a d  mi nist er e d   GI s y  m pt o  m s c al es  d ail y  usi n g  e -di ari es.  
I n  P art   A  a n d  P art   B, s u bj e cts   m e eti n g t h e  eli gi bilit y  crit eri a   will  b e r a n d o  mi z e d i n  a  1: 1 r ati o t o 
o n e  of t  w o  bli n d e d tr e at  m e nt  gr o u ps  as f oll o  ws: 
•    Gr o u p  1:   A L  K S  8 7 0 0  4 6 2   m g   BI  D (  wit h  1  -w e e k titr ati o n)   
•    Gr o u p  2:   D  M F  2 4 0   m g   BI  D (  wit h  1  -w e e k titr ati o n)   
I n  e a c h  p art,  b ot h   A L  K S  8 7 0 0  a n d   D  M F   will  b e  a d  mi nist er e d  or all y   BI  D  as  bli n d e d st u d y  dr u g; 
eit h er   A L  K S  8 7 0 0  4 6 2   m g   BI  D  or   D  M F  2 4 0   m g   BI  D   wit h  a n i niti al  1-  w e e k  d os e titr ati o n  p eri o d. 
S u bj e cts   will  b e i nstr u ct e d t o t a k e st u d y   dr u g   wit h  or   wit h o ut f o o d. H o  w e v er  , s u bj e cts   will  b e 
i nstr u ct e d t o  a v oi d t a ki n g st u d y  dr u g   wit h  a  hi g h-f at,  hi g h-c al ori e   m e al.    D osi n g is  d es cri b e d i n 
d et ail i n  Pr ot o c ol  S e cti o n  9. 1. 
T h e st u d y  d ur ati o n f or  e a c h  p art is  a p pr o xi  m at el y  1 1  w e e ks  ,   w hi c h i n cl u d es  u p t o  4 w e e ks f or 
s cr e e ni n g (i n cl u di n g  a  1 -w e e k l e a d  -i n  p eri o d),  a  5-  w e e k  d o u bl e- bli n d tr e at  m e nt  p eri o d (  wit h 
1-  w e e k titr ati o n),  a n d  a  2- w e e k f oll o  w  - u p  p eri o d (f or s u bj e cts  n ot  c o nti n ui n g i nt o t h e 
A L  K 8 7 0 0-  A 3 0 1 l o n g-t er  m s af et y st u d y).   D uri n g t h e  5-  w e e k t  r e at  m e nt  p eri o d (  Visits  3- 8), 




Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  9  of  3 7  
 
T a bl e  1:   
S c h e d ul e  of   Visits  a n d   Ass ess  m e nts  
 
S c r e e ni n g  
5- W e e k   R a n d o  mi z e d   T r e at  m e nt 1 
F oll o  w -
u p  
Visit   
1 2 
2 3   
3   
4   
5   
6   
7   
8 
(  E  T) 
9 
W e e k 
- 4   
- 1 
( ± 2 
d a ys)  
1 
( ± 3 
d a ys)  
2 
( ± 3 
d a ys)  
3 
( ± 3 
d a ys)  
4 
( ± 3 
d a ys)  
5 
( ± 3 
d a ys)  
6 
( ± 3 
d a ys)  
8 
( ± 4  
d a ys)  
I nf or  m e d   C o ns e nt 
X   
   
   
   
   
   
   
   
 
Eli gi bilit y   Crit eri a   R e vi e  w  
X   
   
X 4   
   
   
   
   
   
 
D e  m o gr a p hi cs   
X   
   
   
   
   
   
   
   
 
M e di c al   Hist or y   
X   
   
   
   
   
   
   
   
 
H ei g ht   
X   
   
   
   
   
   
   
   
 
W ei g ht   
X   
   
X 4   
   
   
   
   
X   
 
P h ysi c al  E x a  m 5 
X   
   
X 4   
   
   
   
   
X   
X 
C o n c o  mit a nt   M e di c ati o n   R e vi e  w   
X   
X   
X   
X   
X   
X   
X   
X   
X 
A d v ers e  E v e nt   M o nit ori n g   
X   
X   
X   
X   
X   
X   
X   
X   
X 
S er ol o g y  T esti n g 6 
X   
   
   
   
   
   
   
   
 
Pr e g n a n c y  T est 7 
X   
   
X 4 
   
   
   
   
   
 
Vit al  Si g ns 8 
X   
   
X 4   
X   
X   
X   
X   
X   
X 
St a n d ar d  1 2 -L e a d  E  C  G 9 
X   
   
X 4   
   
X   
   
   
X   
X 
Bi o c h e  mistr y,   Uri n al ysis,   &   H e  m at ol o g y 
S a  m pl es 1 1 
X   
   
X 4   
   
X   
   
   
X   
X 
 






Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  1 2  of  3 7  
 
2.    
S  A  M P  L  E  SI  Z E   A  N  D  S  T  A  TI S  TI  C  A  L  P  O  W  E  R   C  O  N SI  D E  R  A  TI  O  N 
  
S a  m pl e  Si z e   C o nsi d e r ati o ns ( P a rt   A  a n d  P a rt   B):  T h e s a  m pl e si z e  c al c ul ati o n f or  P art   B is 
b as e d  o n t h e s e c o n d ar y  e n d p oi nt  of t h e   m e a n  n u  m b er  of  d a ys   wit h  a n y I  GI SI S i n di vi d u al 
s y  m pt o  m i nt e nsit y s c or e  ≥ 2. 
Ass u  mi n g t h e   m e a n  n u  m b er  of  d a ys   wit h  a n y I  GI SI S i n di vi d u al s y  m pt o  m i nt e nsit y s c or e  ≥ 2 is 
3. 5  a n d  2. 0 f or t h e   D  M F  a n d   A L  K S  8 7 0 0 tr e at  m e nt  gr o u ps, r es p e cti v el y,  a s a  m pl e si z e  of  5 0 0, 
i n cl u di n g  6 0 r a n d o  mi z e d s u bj e cts  p er  gr o u p ( 1 2 0 s u bj e cts i n t ot al) i n  P art   A  a n d  1 9 0 r a n d o  mi z e d 
s u bj e cts  p er  gr o u p ( 3 8 0  s u bj e cts i n t ot al) i n  P art   B,   will  pr o vi d e  at l e ast  8 0  %  p o  w er t o  d et e ct 
a b o ut  a  4 2  % r e d u cti o n i n t h e  n u  m b er  of  d a ys   wit h  a n y I  GI SI S i n di vi d u al s y  m pt o  m i nt e nsit y 
s c or e  ≥ 2 f or t h e   A L  K S  8 7 0 0 tr e at  m e nt  gr o u p r el ati v e t o t h e   D  M F tr e at  m e nt  gr o u p,  at  a n  al p h a 
l e v el  of  0. 0 5 (t  w o-si d e d)  usi n g  a  n e g ati v e  bi n o  mi al r e gr essi o n  a p pr o a c h.  T h e s a  m pl e si z e 
c al c ul ati o n  ass u  m es  a st a n d ar d  d e vi ati o n  of  5. 9 i n t h e  n u  m b er  of  d a ys   wit h  a n y I  GI SI S i n di vi d u al 
s y  m pt o  m i nt e nsit y s c or e  ≥ 2 r el ati v e t o  e x p os ur e  d a ys f or t h e   D  M F tr e at  m e nt  gr o u p i n  P art   A  a n d 
P art   B.  
Ass u  mi n g t h e   m e a n  n u  m b er  of  d a ys   wit h  a n y I  GI SI S i n di vi d u al s y  m pt o  m i nt e nsit y s c or e  ≥ 2 is 
3. 5  a n d  2. 0 f or t h e   D  M F  a n d   A L  K S  8 7 0 0 tr e at  m e nt  gr o u ps, r es p e cti v el y,   a s a  m pl e si z e  of  3 8 0 
r a n d o  mi z e d s u bj e cts ( 1 9 0 s u bj e cts  p er tr e at  m e nt  gr o u p) i n  P art   B   will  pr o vi d e  at l e ast  8 0  % 
p o  w er t o  d et e ct  a b o ut  a  4 2  % r e d u cti o n i n t h e  n u  m b er  of  d a ys   wit h  a n y I  GI SI S i n di vi d u al 
s y  m pt o  m i nt e nsit y s c or e  ≥ 2 f or t h e   A L  K S  8 7 0 0 tr e at  m e nt  gr o u p r el ati v e t o t h e   D  M F tr e at  m e nt 
gr o u p,  at  a n  al p h a l e v el  of  0. 0 5 (t  w o-si d e d)  usi n g  a  n e g ati v e  bi n o  mi al r e gr essi o n  a p pr o a c h.  T h e 
s a  m pl e si z e  c al c ul ati o n  ass u  m es  a st a n d ar d  d e vi ati o n  of  5. 9 i n t h e  n u  m b er  of  d a ys   wit h  a n y 
I  GI SI S i n di vi d u al s y  m pt o  m i nt e nsit y s c or e  ≥ 2 r el ati v e t o  e x p os ur e  d a ys f or t h e   D  M F tr e at  m e nt 
gr o u p i n  P art   B. 
 
 
 
 
 
 
 
 
 
 
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  1 3  of  3 7  
 
3.    
D  A  T  A   A  N  A  L  Y SI S   
3. 1.    
G e n e r al  St atisti c al   M et h o d ol o g y   
T h e s af et y  a n d  effi c a c y  e n d p oi nts   will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all  as 
d es cri b e d  b el o  w.  I n  g e n er al, s u  m  m ar y st atisti cs ( n,   m e a n, st a n d ar d  d e vi ati o n  [ S  D],   m e di a n, 
mi ni  m u  m  ,  a n d   m a xi  m u  m f or  c o nti n u o us  v ari a bl es,  a n d  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts i n 
e a c h  c at e g or y f or  c at e g ori c al  v ari a bl es)   will  b e  pr o vi d e d  b y tr e at  m e nt  gr o u p   a n d  o v er all. All 
s u  m  m ar y t a bl es   will b e  b as e d  o n  o bs er v e d  d at a,  a n d   missi n g  v al u es   will  n ot  b e i  m p ut e d  u nl ess 
ot h er  wis e i n di c at e d.   M e as ur e  m e nts  c oll e ct e d fr o  m  u ns c h e d ul e d  visits  or r e p e at e d  ass ess  m e nts 
will  n ot  b e i n cl u d e d i n t h e  b y-  visit s u  m  m ar y t a bl es  or fi g ur es,  b ut   will  b e i n cl u d e d i n  t h e 
a n al ys es f or t h e  p ot e nti all y  cli ni c all y si g nifi c a nt ( P  C S ) p ost- b as eli n e  v al u es  a n d s u bj e ct listi n gs. 
S o ur c e  d at a f or t h e s u  m  m ar y t a bl es  a n d st atisti c al  a n al ys es   will  b e  pr es e nt e d  as  b y -s u bj e ct  d at a 
listi n gs. 
B as eli n e  v al u e is  d efi n e d  as t h e l ast  n o n  -missi  n g  ass ess  m e nt  pri or t o t h e first  d os e  of st u d y  dr u g. 
All st atisti c al t ests  a n d  c o nfi d e n c e i nt er v als (  CIs),  u nl ess st at e d  ot h er  wis e,   will  b e  2  -si d e d  a n d 
will  b e s et  at  a n  al p h a l e v el  of  0. 0 5. 
All t h e  effi c a c y  a n al ys es   will  b e s u  m  m ari z e d  b y t h e  pl a n n e d tr e at  m e nt  assi g n  m e nt,  a n d  all t h e 
s af et y  a n al ys es   will  b e s u  m  m ari z e d  b y  a ct u al tr e at  m e nt.  
T h e  d at a   will  b e s u  m  m ari z e d f or t h e f oll o  wi n g t  w o st u d y  p eri o ds  as  a p pr o pri at e. 
•    Tr e at  m e nt  P eri o d,   w hi c h is  d efi n e d  as t h e  p eri o d  b et  w e e n t h e first  d os e  d at e   aft er 
r a n d o  mi zati o n   a n d t h e l ast  d os e  d at e  pl us  1  d a y, i n cl usi v e.  
•    F oll o  w- u p  P eri o d,   w hi c h  is  d efi n e d  as t h e p eri o d  b et  w e e n t h e  d at e  of t h e l ast  d os e 
d at e   pl us  2  d a y  a n d t h e l ast st u d y d at e , i n cl usi v e. 
 
3. 2.    
St u d y  P o p ul ati o n s 
3. 2. 1.    
D efi niti o ns  of   A n al ysis  P o p ul ati o ns (  A n al ysis   S ets)  
3. 2. 1. 1.    S af et y  P o p ul ati o n 
T h e s af et y  p o p ul ati o n  will   i n cl u d e  all r a n d o  mi z e d s u bj e cts   w h o r e c ei v e  at l e ast  o n e  d os e  of st u d y 
dr u g (  A L  K S   8 7 0 0  or   D  M F). 
3. 2. 1. 2.    F ull  A n al ysis  S et ( F  A S)   
T h e f ull  a n al ysis s et ( F  A S)  p o p ul ati o n  will   i n cl u d e  all s u bj e cts   w h o r e c ei v e  at l e ast  o n e  d os e  of 
st u d y  dr u g  a n d   w h o  c o  m pl et e  at l e ast  o n e  p ost  b as eli n e  GI t ol er a bilit y  ass ess  m e nt   (  G  GI SI S  or 
I  GI SI S). 








Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  1 7  of  3 7  
 
 
 
 
 
3. 6. 2. 1.    I n di vi d u al   GI  S y  m pt o  m  a n d I  m p a ct  S c al e 
T h e I  GI SI S is  d esi g n e d t o  ass ess t h e i n ci d e n c e, i nt e nsit y,  o ns et,  d ur ati o n,  a n d f u n cti o n al i  m p a ct 
of  5 i n di vi d u al   GI s y  m pt o  ms:  n a us e a,  v o  miti n g,  u p p er  a b d o  mi n al  p ai n, l o  w er  a b d o  mi n al  p ai n, 
a n d  di arr h e a.  T his s c al e   will  b e s u bj e ct - c o  m pl et e d  usi n g  e-di ari es.  T h es e  5 s y  m pt o  ms   w er e 
i n cl u d e d i n t h e I  GI SI S  as t h e y   w er e t h e   m ost  c o  m  m o nl y r e p ort e d   GI s y  m pt o  ms i n t h e  T e cfi d er a®  
P h as e  3  pl a c e b o - c o ntr oll e d tri als.  S u bj e cts   will  b e  as k e d t o r at e t h e s e v erit y  of  e a c h i n di vi d u al 
s y  m pt o  m  vi a  a n  1 1- p oi nt  n u  m eri c r ati n g s c al e r a n gi n g fr o  m  0 ( di d  n ot  h a v e) t o  1 0 ( e xtr e  m e). 
S u bj e cts   will  als o  b e  as k e d t o i n di c at e t h e st a rt  a n d st o p ti  m es  of  e a c h   GI s y  m pt o  m.   A d diti o n all y, 
s u bj e cts   will  b e  as k e d t o i n di c at e  h o  w   m u c h  e a c h s y  m pt o  m  h as i nt erf er e d   wit h t h eir  a bilit y t o 
a c c o  m plis h t h eir r e g ul ar  d ail y  a cti viti es  usi n g  a  5 -p oi nt  Li k ert s c al e ( n ot  at  all, sli g htl y, 
m o d er at el y,  q uit  e  a  bit,  e xtr e  m el y) . 
GI t ol er a bilit y  ass ess  m e nt  utili zi n g   t h e I  GI SI S   will f o c us  o n i nt e nsit y s c or es ( 1 1  p oi nt  n u  m eri c 
s e v erit y r ati n g s c al e)  of  e a c h i n di vi d u al s y  m pt o  m. If  a n I  GI SI S  s y  m pt o  m is r e c or d e d  as o n g oi n g, 
o nl y t h e  i niti al i nt e nsit y s c or e will  b e   c oll e ct e d (i. e., l o gi c all y s ki p p e d it e  m)  a n d t h e  i niti al 
i nt e nsit y s c or e  c oll e ct e d  at t h e s y  m pt o  m st art   will  b e  c arri e d  o v er  u ntil s y  m pt o  m  e n d. 
 
N u  m b er  of  d a ys   wit h  a n y I  GI SI S i n di vi d u al s y  m pt o  m i nt e nsit y s c or e  ≥ 2   r el ati v e t o  e x p os ur e 
d a ys  
N u  m b er  of  d a ys   w  it h  a n y I  GI SI S i n di vi d u al s y  m pt o  m i nt e nsit y s c or e  ≥ 2 ( e v e nt  d a ys) is  c o u nt e d 
a  m o n g  o bs er v e d  di ari es.  E x p os ur e  d a ys  ar e  t h e n u  m b er  of  d a ys  b et  w e e n  a s u bj e ct ’s first  d os e 
d at e  a n d  l ast  d os e  d at e  d uri n g tr e at  m e nt  p eri o d, i n cl usi v e.  
L et θ  ( 1) a n d 𝜃  ( 2)  d e n ot e t h e   m e a n  n u  m b er  of  d a ys   wit h  a n y I  GI SI S i n di vi d u al s y  m pt o  m i nt e nsit y 
s c or es  ≥  2, f or   A L  K S  8 7 0 0  a n d   D  M F, r es p e cti v el y.  C o  m p aris o n  of   GI t ol er a bilit y   will  b e t est e d 
at  5  % l e v el  of si g nifi c a n c e  i n a t  w o -si d e d t est, t hr o u g h t h e f oll o  wi n g  h y p ot h esis  of  no tr e at  m e nt 
eff e ct:   
H 0: 𝜃  ( 1) = 𝜃  ( 2)   vs.   H a: 𝜃  ( 1)  ≠𝜃  ( 2) 
A L  K S  8 7 0 0   will  b e   cl ai  m e d s u p eri or  t o   D  M F if t h e  esti  m at e d θ  ( 1) is l ess t h a n t h e  esti  m at e d 𝜃  ( 2) 
a n d   p- v al u e is l ess t h a n  0. 0 5 (i n  a  2- si d e d t est). D  M F   will  b e   cl ai  m e d s u p eri or  t o   A L  K S  8 7 0 0 if 
t h e  esti  m at e d θ  ( 2) is l ess t h a n t h e  esti  m at e d 𝜃  ( 1)  a n d  p- v al u e is l ess t h a n  0. 0 5 (i n  a  2-si d e d t est).   
E v e nt  d a ys   will  b e  a n al y z e d  b y t h e  n e g ati v e  bi n o  mi al r e gr essi o n   m o d el, i n cl u di n g   tr e at  m ent  as 
f a ct or a n d  a dj usti n g f or s t u d y p arts  ( n ot i n cl u d e d i n p art   B  o nl y  a n al ys es) , r e gi o n (  U S  a n d  n o n-
U S)  , a g e   a n d B o d y   M ass I n d e x (  B  MI  ).   A d diti o n al  c o v ari at es   m a y  als o  b e i n cl u d e d i n t h e   m o d el. 
T h e l o g arit h  mi c tr a nsf or  m ati o n  of  e x p os ur e  d a ys   will  b e i n cl u d e d i n t h e   m o d el  as t h e  “ offs et ” 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  1 8  of  3 7  
 
p ar a  m et er.  If t h e  d at a  ar e  u n d er dis p ers e d,  or if t h e  n e g ati v e  bi n o  mi al r e gr essi o n   m o d el  d o es  n ot 
c o n v er g e,  a  P oiss o n r e gr essi o n   m o d el   wit h t h e s a  m e  c o v ari at es   will  b e  us e d i nst e a d  of t h e 
n e g ati v e  bi n o  mi al r e gr essi o n   m o d el.   Dis p ersi o n   will  b e  e v al u at e d fr o  m t h e  P e ars o n   C hi-s q u ar e 
st atisti c. If t h e r ati o  of t h e  P e ars o n   C hi -sq u ar e  st atisti c t o t h e  d e gr e es  of fr e e d o  m is  ≤  1   w hi c h 
i n di c at es  n o  o v er dis p ersi o n, t h e n  a  P oiss o n r e gr essi o n   m o d el   wit h  a dj ust  m e nt f or 
u n d er dis p ersi o n   will  b e  us e d.   C o u nt  distri b uti o ns i n   w hi c h t h e  n u  m b er  of i nt er v als   wit h  z er o 
e v e nts is  hi g h er t h a n  pr e di ct e d  b y  a  N e g ati v e  bi n o  mi al  or   P oiss o n   m o d el   m a y  b e   m o d el e d  usi n g  a 
Z er o -i nfl at e d   m o d el. 
T his   m et h o d   will  als o  b e  us e d f or t h e s e c o n d ar y  e n d p oi nts  b y  s etti n g t h e   GI s y  m pt o  m i nt e nsit y 
s c or e  c ut  off  as   1  a n d  3.  Em piri c al  c u  m ul ati v e  distri b uti o n f u n cti o n    pl ot  of  n u  m b er  of  e v e nt  d a ys 
b y  tr e at  m e nt  gr o u ps   will  b e  pr es e nt e d.  
 
W orst I  GI SI S s y  m pt o  m i nt e nsit y s c or e  b y   w e e k  d uri n g t h e  5   w e e k tr e at  m e nt  p eri o d 
W orst   i n di vi d u al I  GI SI S sy  m pt o  m  i nt e nsit y s c or e is  d efi n e d  as  a s u bj e ct’s   w orst (i. e.,  hi g h est) 
s y  m pt o  m i nt e nsit y s c or e  f or  a n y s y  m pt o  m  o ut  of  all  c o  m pl et e d I  GI SI S  di ari es  d uri n g  a  gi v e n  
p eri o d.  W orst   I  GI SI S s y  m pt o  m i nt e nsit y s c or es  b y   w e e k  d uri n g t h e  5   w e e k tr e at  m e nt  p eri o d  f or 
e a c h  s u bj e ct   will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u ps  a n d   will  b e  a n al y z e d  usi n g  a n  A n al ysis  of 
c o v ari a n c e  (A  N  C  O  V  A  )   m o d el.  T h e m o d el   will i n cl u d e tr e at  m e nt   as f a ct or s,  a n d  a dj usti n g f or 
st u d y  p arts, r e gi o n (  U S  a n d  n o n-  U S),  a g e  a n d   B  MI.   A d diti o n al  c o v ari at es   m a y  a ls o  b e i n cl u d e d. 
 
W orst I  GI SI S i n di vi d u al s y  m pt o  m i nt erf er e n c e   l e v el 
W orst I  GI SI S   i n di vi d u al sy  m pt o  m  i nt erf er e n c e l e v el is  d efi n e d  as  a s u bj e ct’s   w orst s y  m pt o  m 
i nt erf er e n c e l e v el (  No s y  m pt o  m  <   N ot  at  all  <  Sli g htl y  <   M o d er at el y  <   Q uit e  a  bit  <  E xtr e  m el y)   
f or  a  p arti c ul ar s y  m pt o  m  o ut  of  all  c o  m pl et e d I  GI SI S  di ari es  d uri n g  t h e tr e at  m e nt  p eri o d. All   fi v e 
GI s y  m pt o  ms   ( n a us e a,  v o  miti n g,  u p p er  a b d o  mi n al  p ai n, l o  w er  a b d o  mi n al  p ai n  a n d  di arr h e a) will 
b e r e p ort e d  s e p ar at el y  a n d s u  m  m ari z e d  b y tr e at  m e nt  gr o u ps. 
 
S e nsiti vit y   A n al ysis  of I  GI SI S  E n d p oi nts 
A n  e v al u a bl e  di ar y is  d efi n e d  as  a n i nst a n c e   w h e n  a s u bj e ct t o o k st u d y  dr u g  pri or t o  c o  m pl eti n g 
t h e  di ar y  a n d  c o  m pl et e d t h e  di ar y   wit hi n t h e r e c o  m  m e n d e d r e p orti n g   wi n d o  w ( 2 t o  9  h o urs  p ost-
d os e).  S u  m  m ar y st atisti cs  will  b e  pr es e nt e d f or I  GI SI S  pri  m ar y  a n d s e c o n d ar y  e n d p oi nt   b y 
e v al u a bl e  a n d  n o n- e v al u a bl e  d airi es.  E v e nt  d a ys  will  b e  a n al y z e d  c o ntr olli n g f or  e v al u a bl e  a n d 
n o n- e v al u a bl e  d airi es.  
 
3. 6. 2. 2.    Gl o  b al   GI  S y  m pt o  m  a n d I  m p a ct  S c al e   
T h e   G  GI SI S is  a  gl o b al s c al e t o  ass ess  t h e  o v er all i nt e nsit y,  b ot h ers o  m e n ess,  a n d f u n cti o n al 
i  m p a ct  of   GI s y  m pt o  ms  e x p eri e n c e d  d uri n g t h e  pr e vi o us  2 4  h o urs.  T his s c al e   will  b e s u bj e ct-
c o  m pl et e d  usi n g  e- di ari es.  S u bj e cts   will  b e  as k e d t o r at e t h e i nt e nsit y  a n d  b ot h ers o  m e n ess  of   GI 
s y  m pt o  ms  e x p eri e n c e d  usi n g  a n  1 1- p oi nt  n u  m eri c r ati n g s c al e.   A d diti o n all y, s u bj e cts   will  b e 
as k e d t o i n di c at e:   


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  1 9  of  3 7  
 
•    H o  w   m u c h t h eir   GI s y  m pt o  ms  h a v e i nt erf er e d   wit h t h eir  a bilit y t o  a c c o  m plis h t h eir 
r e g ul ar  d ail y  a cti viti es  usi n g  a  5-p oi nt  Li k ert s c al e ( n ot  at  all, sli g htl y ,   m o d er at el y, 
q uit e  a  bit,  e xtr e  m el y),  
•    N u  m b er  of  h o urs  of   w or k   miss e d  d u e t o   GI s y  m pt o  ms, 
•    I  m p a ct  of   GI s y  m pt o  ms  o n   w or k  pr o d u cti vit y  usi n g  a  5-p oi nt  Li k ert s c al e ( n ot  at  all, 
sli g htl y,   m o d er at el y,  q uit e  a  bit,  e xtr e  m el y). 
 
N u  m b er  of  d a ys   wit h  a   G  GI SI S s y  m pt o  m i nt e nsit y s c or e  ≥ 2 r el ati v e t o  e x p os ur e  d a ys 
N u  m b er  of  d a ys   wit h  a   G  GI SI S s y  m pt o  m i nt e nsit y s c or e  ≥ 2 ( e v e nt  d a ys)  is  c o u nt e d  a  m o n g 
a v ail a bl e  di ari es.  E x p os ur e  d a ys  ar e  t h e n u  m b er  of  d a ys  b et  w e e n  a s u bj e ct ’s first  d os e d at e   pl us 
o n e  a n d  l ast  d os e  d at e d uri n g tr e at  m e nt  p eri o d , i n cl usi v e.  
E v e nt  d a ys   will  b e  a n al y z e d  b y t h e  n e g ati v e  bi n o  mi al r e gr essi o n   m o d el,   usi n g tr e at  m e nt  as 
f a ct ors  a n d  a dj usti n g f or st u d y p arts ( n ot  i n cl u d e d i n p art   B  o nl y  a n al ys es) , r e gi o n (  U S  a n d  n o n-
U S),  a g e  a n d   B  MI.   A d diti o n al  c o v ari at es   m a y  als o  b e i n cl u d e d i n t h e   m o d el.   T h e l o g arit h  mi c 
tr a nsf or  m ati o n  of  e x p os ur e  d a ys will  b e i n cl u d e d i n t h e   m o d el  as t h e  “ offs et ”  p ar a  m et er. If t h e 
d at a  ar e  u n d er dis p ers e d,  or if t h e  n e g ati v e  bi n o  mi al r e gr essi o n   m o d el  d o es  n ot  c o n v er g e ,  a 
P oiss o n r e gr essi o n   m o d el   wit h t h e s a  m e  c o v ari at es   will  b e  us e d i nst e a d  of t h e  n e g ati v e  bi n o  mi al 
r e gr essi o n   m o d el.   Dis p ersi o n   will  b e  e v al u at e d fr o  m t h e  P e ars o n   C hi-sq u ar e st atisti c. If t h e r ati o 
of t h e  P e ars o n   C hi-s q u ar e st atisti c t o t h e  d e gr e es  of fr e e d o  m is  ≤  1   w hi c h i n di c at es  n o 
o v er dis p ersi o n, t h e n  a  P oiss o n r e gr essi o n   m o d el   wit h  a dj ust  m e nt f or  u n d er dis p ersi o n   will  b e 
us e d.   C o u nt  distri b uti o ns i n   w hi c h t h e  n u  m b er  of i nt er v als   wit h  z er o  e v e nts is  hi g h er t h a n 
pr e di ct e d  b y  a  N e g ati v e  bi n o  mi al  or   P oiss o n   m o d el   m a y  b e   m o d el e d  usi n g  a  Z er o- i nfl at e d 
m o d el. 
T his   m et h o d   will  als o  b e  us e d f or t h e s e c o n d ar y  e n d p oi nts  b y  s etti n g t h e   GI s y  m pt o  m i nt e nsit y 
s c or e  c ut  off  as  1  a n d  3.  E  m piri c al  c u  m ul ati v e  distri b uti o n f u n cti o n  pl ot  of  n u  m b er  of  e v e nt  d a ys 
b y  tr e at  m e nt  gr o u ps   will  b e  pr es e nt e d. 
 
W orst   G  GI SI S  b ot h ers o  m e s c or e  a n d i nt erf er e n c e l e v el   
S u bj e ct’s   w orst  G  GI SI S    b ot h ers o  m e s c or e  a n d   w orst i nt erf er e n c e l e v el (N  o  S y  m pt o  m  <   N ot  at 
all  <  Sli g htl y  <   M o d er at el y  <   Q uit e  a  bit  <  E xtr e  m el y)   o ut  of  all  c o  m pl et e d I  GI SI S  d i ari es 
d uri n g  t h e tr e at  m e nt  p eri o d will  b e   s u  m  m ari z e d  b y tr e at  m e nt  gr o u ps.  
 
3. 6. 3.    
Ot h e r   E x pl o r at o r y   E n d p oi nts   
 






Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2 2  of  3 7  
 
will  b e s u  m  m ari z e d  usi n g  d es cri pti v e st atisti cs  al o n g   wit h s u p p orti v e listi n gs  b as e d  o n  o bs er v e d 
v al u es.  Listi n gs   will  b e  pr o vi d e d f or  all s af et y  p ar a  m et ers.  
3. 7. 1.    
A d v e rs e   E v e nts   
All  a d v ers e  e v e nts (  A Es)   will  b e  c o d e d  b y  S yst e  m   Or g a n   Cl ass   ( S  O  C) a n d  Pr ef err e d  T er  m  ( P T) 
usi n g t h e   M e di c al   Di cti o n ar y f or  R e g ul at or y   A cti viti es   M e d  D  R  A  v ersi o n  2 0. 1  .  T h e  v er b ati  m 
t er  m   will  b e i n cl u d e d i n t h e   A E listi n gs. 
A Es   will  b e i d e ntifi e d  as  e  m er gi n g i n t h e tr e at  m e nt  p eri o d  a n d t h e f oll o  w  u p  p eri o d.   D uri n g t h e 
tr e at  m e nt  p eri o d,  an   A E   will  b e  c o nsi d er e d  a tr e at  m e nt -e  m er g e nt   A E ( T E  A E) if t h e  e v e nt  st arts 
or   w ors e ns  o n  or  aft er t h e  d at e  of first  d os e  of st u d y  d r u g i n t h e  c urr e nt tri al. T h e  Tr e at  m e nt 
P eri o d is  d efi n e d  as t h e  p eri o d fr o  m t h e first  d os e  d at e t o  l ast  d os e  d at e  pl us  1  d a y, i n cl usi v e. 
D uri n g t h e f oll o  w  u p  p eri o d,  p ost- dis c o nti n u ati o n  e  m er g e nt   A Es (  P  D E  A Es) , d efi n e d  as   A Es t h at 
st art e d  or   w ors e n e d  aft er  t h e l ast  d os e  d at e  pl us  1  d a y, will  b e s u  m  m ari z e d.  F or   P  D E  A Es, t h e 
gr e at est s e v erit y  o n  or  b ef or e  t h e l ast  d os e d at e   pl us  1  d a y will  b e  us e d  as t h  e  b e n c h  m ar k f or t h e 
c o  m p aris o n  of t h e   A Es  o c c urri n g  d uri n g t h e f oll o  w  u p  p eri o d.  T h e  F oll o  w - u p  P eri o d is  d efi n e d 
as t h e  p eri o d  b et  w e e n t h e  d at e  of t h e  l ast  d os e  d at e  pl us  2  d a y  a n d t h e l ast st u d y d at e , i n cl usi v e.  
A n  o v er vi e  w t a bl e, i n cl u di n g  n u  m b er  of s u bj e cts   wit h   T E  A Es, s eri o us   A Es ( S  A Es),   A Es l e a di n g 
t o st u d y  dis c o nti n u ati o n,  a n d st u d y  dr u g-r el at e d  T E  A Es will  b e   pr o vi d e d.  A d v ers e  e v e nts l e a di n g 
t o st u d y  dis c o nti n u ati o n  a n d  S  A Es l e a di n g t o  d e at h   will  b e s u  m  m ari z e d i n t h e  p eri o d   w h e n t h e 
dis c o nti n u ati o n  or  d e at h  o c c urr e d. 
T h e f oll o  wi n g s u  m  m ar y t a bl es   will  b e  pr o vi d e d f or t h e tr e at  m e nt  p eri o d  b y   tr e at  m e nt gr o u p  a n d 
o v er all:   
•    T E  A Es  b y  S  O  C   a n d P T   
•    T E  A Es  b y  S  O  C , P T ,  a n d s e v erit y  
•    T E  A Es  b y  S  O  C , P T ,  a n d r el ati o ns hi p 
•    St u d y  dr u g r el at e d  T E  A Es  b y  S  O  C  a n d  P T   
•    T E  A Es  e x p eri e n c e d  b y  ≥ 5  %  of s u bj e cts  b y  S  O  C   a n d P T  
•    T E  A Es  e x p eri e n c e d  b y  ≥ 2  %  of s u bj e cts  b y  S  O  C   a n d P T  
•    S  A Es  b y  S  O  C   a n d P T   
•    A Es l e a di n g t o st u d y  dis c o nti n u ati o n  b y   S  O  C   a n d P T  
All   A E t a bl es   will  b e s ort e d  b y   S  O  C   a n d t h e n P T  i n  d e cr e asi n g fr e q u e n c y  b as e d  o n  all s u bj e cts i n 
t h e  S af et y  P o p ul ati o n. 
A s u bj e ct  h a vi n g t h e s a  m e   A E ( as  d et er  mi n e d  b y t h e  c o d e d   M e d  D  R  A   P T )   m or e t h a n  o n c e   will 
b e  c o u nt e d  o nl y  o n c e i n t h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts'  c al c ul ati o n f or t h at   A E. 
Si  mil arl y, if  a s u bj e ct  h as   m or e t h a n  o n e   A E i n  a n  S  O  C, t h e s u bj e ct   will  b e  c o u nt e d  o nl y  o n c e i n 
t h e t ot al  n u  m b er  of s u bj e cts   wit h  a n   A E f or t h at  S  O  C. If a s u bj e ct  h as t h e s a  m e   A E  o n   m ulti pl e 
o c c asi o ns, t h e  hi g h est s e v erit y (s e v er e  >   m o d er at e  >   mil d) r e c or d e d f or t h e  e v e nt   will  b e 
pr es e nt e d i n t h e   A E  b y s e v erit y s u  m  m ar y.  Si  mil arl y, if  a s u bj e ct  h as t h e s a  m e   A E  o n   m ulti pl e 
o c c asi o ns, t h e  cl os est r el ati o ns hi p t o st u d y  dr u g  (r el at e d  >  n ot r el at e d,   w h er e r el at e d i n cl u d es 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2 3  of  3 7  
 
d efi nit el y r el at e d,  pr o b a bl y r el at e d,  a n d  p ossi bl y r el at e d;  a n d  n ot r el at e d i n cl u d es  pr o b a bl y  n ot 
r el at e d  a n d  d efi nit el y  n ot r el at e d) r e c or d e d f or t h e  e v e nt   will  b e  pr es e nt e d i n t h e   A E  b y 
r el ati o ns hi p s u  m  m ar y.  
T h e f oll o  wi n g s u  m  m ar y t a bl es   will  b e  pr o vi d e d f or fl us hi n g  a n d fl us hi n g-  r el at e d  T E  A Es  a n d GI 
S  O  C   o nl y b y  tr e at  m e nt  gr o u p  a n d  o v er all:  
•    T E  A Es  b y  P T   a n d  o ut c o  m e 
•    D ur ati o n  of  T E  A Es  a  m o n g t h os e r es ol v e d  b y   P T    
•    Ti  m e t o  o ns et  of  T E  A Es  b y  P T  
P T s f or fl us hi n g  a n d r el at e d   A Es i n cl u d e: fl us hi n g;  h ot fl us h;  er yt h e  m a,  g e n er ali z e d  er yt h e  m a, 
b ur ni n g s e ns ati o n, s ki n  b ur ni n g s e ns ati o n, f e eli n g  h ot,  pr urit us;  pr urit us  g e n er ali z e d; r as h, r as h 
pr uriti c, r as h   m a c ul o- p a p ul ar; r as h   m a c ul ar; r as h  p a p ul ar.  
If  a su bj e ct  h as t h e s a  m e   A E  o n   m ulti pl e  o c c asi o ns, t h e   w orst  o ut c o  m e ( n ot r es ol v e d  > r es ol v e d, 
w h er e r es ol v e d i n cl u d es r  e c o v er e d/ r es ol v e d  a n d re c o v er e d/ res ol v e d   wit h  s e q u el a e;  a n d  n ot 
r es ol v e d i n cl u d es  n ot r e c o v er e d/ n ot r es ol v e d  a n d f at al) r e c or d e d f or t h e  e v e n t   will  b e  pr es e nt e d 
i n t h e   A E  b y  o ut c o  m e s u  m  m ar y.  F or  d ur ati o n  a n d ti  m e t o  o ns et, if  a s u bj e ct  h as t h e s a  m e   A E  o n 
m ulti pl e  o c c asi o ns, t h e first  pr es e nt ati o n   will  b e  us e d i n s u  m  m ari zi n g   ti  m e t o  o ns et  a n d t h e   m e a n 
d ur ati o n  of t h e   m ulti pl e   A E  e v e nts   will  b e  u s e d i n s u  m  m ari zi n g  d ur ati o n. 
All   A Es   will  b e i n cl u d e d i n t h e listi n gs.    S u p p orti n g listi n gs  of  S  A Es,   A Es l e a di n g t o st u d y 
dis c o nti n u ati o n,  a n d   A Es l e a di n g t o  d e at h   will  b e  pr o vi d e d.  S u bj e cts   wit h  P  D E  A Es  i n t h e 
F oll o  w- u p  P eri o d   will  als o  b e list e d.  
3. 7. 2.    
D e at hs,   S e ri o us  a n d   Ot h e r  Si g nifi c a nt   A d v e rs e   E v e nts  
T h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h  at l e ast  o n e  S  A E (r e g ar dl ess tr e at  m e nt  e  m er g e nt  or 
n ot)   will  b e s u  m  m ari z e d  b y  S  O  C   a n d P T  f or t h e  S af et y  P o p ul ati o n. D e at hs  a n d   A Es l e a di n g t o 
dis c o nti n u ati o n (r e g ar dl es s tr e at  m e nt  e  m er g e nt  or  n o t)   will  b e s u  m  m ari z e d si  mil arl y. 
S u p p orti n g listi n gs  of s eri o us   A Es  a n d   A Es l e a di n g t o st u d y  dis c o nti n u ati o ns   will  b e  pr o vi d e d. 
S u bj e cts   w h o  di e d  d uri n g t h e st u d y   will  als o  b e list e d. 
3. 7. 3.    
A d v e rs e   E v e nts  of  S p e ci al I nt e r est   
A d v ers e  e v e  nts i n  th e  f oll o  wi n g  c at e g ori es  of i nt er est will  b e  pr es e nt e d  b y   f oll o  wi n g  c at e g ori es 
a n d  P T s: 
•    A n a p h yl a xis  a n d   A n gi o e d e  m a (s eri o us   a d v ers e  e v e nts)  
•    L y  m p h o p e ni a 
•    Li v er I nj ur y     
•    M ali g n a n ci es   a n d  Pr e-  m ali g n a nt   C o n diti o ns 
•    O p p ort u nisti c I nf e cti o ns (  A Es  a n d  S  A Es)  a n d   All  S eri o us I nf e cti o ns (I n cl u di n g 
O p p ort u nisti c I nf e cti o ns  S  A Es)   
•    P a n cr e atitis  


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2 4  of  3 7  
 
•    R e n al   I nj ur y   
•    C ar di a c   Dis or d ers     
•    G astr oi nt esti n al   T ol er a bilit y    A Es (s eri o us  a d v ers e  e v e nts  a n d  a d v ers e  e v e nts l e a di n g 
t o  dis c o nti n u ati o n) 
•    A b us e  p ot e nti al  
S u p p orti v e   A E listi n gs i n cl u di n g s eri o us  a n d  n o n- s eri o us   A Es will  b e  pr o vi d e d f or  e a c h s p e ci al 
i nt er est  gr o u p.   A d diti o n all y, listi n g f or  “ n o n-s p e cifi c ”   A Es i n t h e  a b us e  p ot e nti al  c at e g or y   will 
b e  pr o vi d e d.   N arr ati v es   will  b e  pr o vi d e d f or  “ e u p h ori a r el at e d ”   a n d  “ a b us e  b e h a vi or ”   A Es i n t h e 
c at e g or y  of   a b us e  p ot e nti al. 
3. 7. 4.    
Cli ni c al   L a b o r at o r y  P a r a  m et e rs   
L a b or at or y  p ar a  m et ers   will  b e  pr es e nt e d i n  c o n v e nti o n al  u nits.   O nl y s c h e d ul e d l a b or at or y 
p ar a  m et ers   will  b e i n cl u d e d i n t h e s u  m  m ari es   of l a b or at or y  d at a.   All l a b or at or y  d at a, i n cl u di n g 
t h os e  c oll e ct e d  at  u ns c h e d ul e d  visits,   will  b e i n cl u d e d i n t h e listi n gs. L a b or at or y r es ults ( b as eli n e 
a n d  c h a n g e fr o  m  b as eli n e) f or  c h e  mistr y ,  h e  m at ol o g y a n d  uri n al ysis  p ar a  m et ers f or  e a c h  visit 
d uri n g t h e  e ntir e st u d y   will  b e s u  m  m ari z e d  b y tr e at  m e nt   gr o u p  a n d  o v er all. 
F or  uri n al ysis,  t h e n u  m b er  of  a b n or  m aliti es  at  a n y  p ost- b as eli n e  visit   will  b e s u  m  m ari z e d. I n 
a d diti o n, t h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h  v al u es  c o nsi d er e d  p ot e nti all y  cli ni c all y 
si g nifi c a nt ( P  C S)  o c c urri n g  at  a n y  p ost -b as eli n e  visit f or s el e ct e d  p ar a  m et ers   will  b e s u  m  m ari z e d 
b y  tr e at  m e nt  gr o u p  a n d  o v er all. 
Cli ni c al l a b or at or y t est  v al u es, s c h e d ul e d  or  u ns c  h e d ul e d   d uri n g t h e tr e at  m e nt  p eri o d,   will  be 
c o nsi d er e d  P  C S  if t h e y   m e et t h e P  C S  crit eri a list e d i n  T a bl e  2 .  T h e  p er c e nt a g es   will  b e 
c al c ul at e d r el ati v e t o t h e  n u  m b er  of s u bj e cts   wit h  a v ail a bl e  n o n -P  C S  b as eli n e  v al u es   wit h r es p e ct 
t o t h e s p e cifi c  crit eri o n  a n d at l e ast  1  p ost -b as eli n e  ass ess  m e nt.  T h e  d e n o  mi n at or  is t h e t ot al 
n u  m b er  of s u bj e cts   wit h  a  n o n- P  C S  b as eli n e  v al u e   wit h r es p e ct t o t h e s p e cifi c  crit eri o n  a n d  at 
l e ast  1  p ostb as eli n e  P  C S   v al u e. A s u p p orti v e listi n g   will  pr es e nt  all  v al u es f or  a  p ar a  m et er f o  r 
s u bj e cts   wit h  at l e ast  o n e  P  C S  v al u e f or t h at  p ar a  m et er.  
S hift t a bl es f or s hift fr o  m   wit hi n  n or  m al r ef er e n c e li  mits /  hi g h t o l o  w  a n d s hift fr o  m   wit hi n 
n or  m al r ef er e n c e li  mits / l o  w t o  hi g h  d uri n g  t h e tr e at  m e nt  p eri o d   will  b e  pr o vi d e d f or  c h e  mistr y 
a n d   he  m at ol o g y  p ar a  m et ers   wit h  c o n v e nti o n al r ef er e n c e li  mits (li  mits  pr o vi d e d  b y t h e 
p erf or  mi n g l a b or at ori es)  b y  tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n.  F or 
p ar a  m et ers   w hi c h  h a v e  g e n d er  a n d /  or  a g e s p e cifi c li  mits, t h e  c at e g ori es   will  b e  b as e d  o n t h e 
s p e cifi c li  mits.   Hi g h is  d efi n e d  as  v al u es  gr e at er t h a n t h e  u p p er li  mit  of t h e r ef er e n c e r a n g e 
(  U L R  R).  L o  w is  d efi n e d  as  v al u es l ess t h a n t h e l o  w er li  mit  of t h e r ef er e n c e r a n g e ( L L  R  R). 
N or  m al r ef er e n c e li  mits is  d efi n e d  as  v al u es   wit hi n  n or  m al r a n g e.    
T h e  p er c e nt a g es   will  b e  c al c ul at e d f or t h e s hift s u  m  m ar y  as f oll o  ws:   
•    F or t h e s hifts fr o  m   wit hi n  n or  m al r ef er e n c e li  mits /  hi g h t o l o  w: t h e  n u  m er at or is 
d efi n e d  as t h e  n u  m b er  of s u bj e cts   wit h  a  p ost- b as eli n e r es ult  b el o  w t h e  L L  R  R,  a n d 
t h e  d e n o  mi n at or is  d efi n e d  as t h e  n u  m b er  of s u bj e cts   wit h  a  b as eli n e  v al u e   wit hi n t h e 
li  mits  or  a b o v e t h e   U L R  R. 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2 5  of  3 7  
 
•    F or t h e s hifts fr o  m   wit hi n  n or  m al r ef er e n c e li  mits / l o  w t o  hi g h: t h e  n u  m er at or is 
d efi n e d  as t h e  n u  m b er  of s u bj e cts   wit h  a  p ost- b as eli n e r es ult   a b o v e t h e   U L  R  R,  a n d 
t h e  d e n o  mi n at or is  d efi n e d  as t h e  n u  m b er  of s u bj e cts   wit h  a  b as eli n e  v al u e   wit hi n t h e 
li  mits  or  b el o  w t h e  L L  R  R. 
T h e f oll o  wi n g  fi g ur es will  b e  pr es e nt e d  b y tr e at  m e nt    gr o u p  a n d  o v er all: 
•    M e a n  al o n g   wit h t h e  c orr es p o n di n g  S E f or   c h a n g e fr o  m  b as eli n e  v al u es f or  s el e ct e d 
c h e  mistr y  a n d  h e  m at ol o g y l a b or at or y  p ar a  m et er s. 
•    B o x pl ots   will  b e  us e d t o  dis pl a y s u  m  m ar y st atisti cs f or t h e   m a xi  m u  m  a n d   mi ni  m u  m 
c h a n g e fr o  m  b as eli n e  v al u es f or s el e ct e d  c h e  mistr y  a n d  h e  m at ol o g y l a b or at or y 
p ar a  m et er s.   
Pr e g n a n c y t est  d at a   will  b e list e d.   
T a bl e   2:  P ot e nti all y   Cli ni c all y  Si g nifi c a nt  ( P  C S) C rit e ri a f o r   L a b o r at o r y  P a r a  m et e rs   
C at e g o r y   
P a r a  m et e r  
C rit e ri a   
H e  m at ol o g y      
H e  m at o crit    
≤ 3 2  %  a n d  3  p oi nt  d e cr e as e fr o  m  b as eli n e 
( F e  m al e) 
≤ 3 7  %  a n d  3  p oi nt  d e cr e as e fr o  m  b as eli n e 
(  M al e) 
H e  m o gl o bi n    
≤ 9. 5  g/ d L ( F e  m al e)  
≤ 1 1. 5  g/ d L (  M al e)  
N e utr o p hils    
< 1. 5  ×  1 0 ^ 3/ u L  
Pl at el ets   
< 7 5. 1  ×  1 0 ^ 3/ u L  
≥ 7 0 0  ×  1 0 ^ 3/ u L   
W  B  Cs   -t ot al,  diff er e nti al ( a bs ol ut e)   
≤ 2. 8  ×  1 0 ^ 3/ u L  
≥ 1 6  ×  1 0 ^ 3/ u L   
E osi n o p hils  
> 1. 0  ×  1 0 ^ 3  c ells/ u L  
L y  m p h o c yt es  
<  0. 5  x  1 0 9/ L 
C h e  mistr y     
A L T   
≥ 3  ×   U L  N  
Al b u  mi n   
< 2. 5  g/ d L  
A L  K- P 
≥ 3  ×   U L  N  
A S T   
≥ 3  ×   U L  N  
Bi c ar b o n at e   
< 1 5   m  m ol/ L  
> 3 1   m  m ol/ L  
B  U  N   
>  3 0   m g/ dl  
C al ci u  m   
< 8. 2   m g/ d L  
> 1 2   m g/ d L  
C hl ori d e   
≤  9 0   m  m ol/ L  
≥  1 1 8   m  m ol/ L  
Cr e ati n e   Ki n a s e   
> 3  ×   U L  N  


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2 6  of  3 7  
 
C at e g o r y   
P a r a  m et e r  
C rit e ri a   
Cr e ati ni n e   
≥ 2   m g/ d L  
Gl u c os e   
<  5 0   m g/ d L  
>  2 0 0   m g/ d L  
H  D L   C h ol e st er ol   
≤  3 0   m g/ d L  
L a ct at e   D e h y dr o g e n as e  
> 3  ×   U L  N  
L  D L   C h ol est er ol  
≥ 1 6 0   m g/ d L  
P h os p h or us  
< 2   m g/ d L  
> 5   m g/ d L  
P ot assi u  m  
< 3   m  m ol/ L  
> 5. 5   m  m ol/ L  
S o di u  m  
< 1 3 0   m  m ol/ L  
> 1 5 0   m  m ol/ L  
T ot al   Bilir u bi n  
≥ 2   m g/ d L  
T ot al   C h ol est er ol  
> 3 0 0   m g/ d L  
Tri gl y c eri d es  
 
≥ 1 2 0   m g/ d L ( F e  m al e)  
≥ 1 6 0   m g/ d L (  M al e)  
Uri c   A ci d   
>  9   m g/ d L  
>  8   m g/ d L ( F e  m al e)  
>  1 0   m g/ d L (  M al e)  
Uri n al ysis     
Gl u c os e   
at l e ast  2 +  
Pr ot ei n  
at l e ast  2 +  
Al b u  mi n/  Cr e ati ni n e    
> 2 0 0  g/ k g  
B et a  -2   Mi cr o gl o b uli n  
> 0. 3 0 0   m g/ L  
F or  a b n or  m al  li v er f u n cti o n t ests, t h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts   will  b e s u  m  m ari z e d  b y 
u p p er li  mit  of  n or  m al (  U L  N)  c at e g or y  as f oll o  ws:    
•    A L T ( al a ni n e  a  mi n otr a nsf er as e),   A S T ( as p art at e  a  mi n otr a nsf er as e)  a n d   A L  K  -P 
( al k ali n e  p h os p h at as e)   will  b e s u  m  m ari z e d  b y  n or  m al,  > 3 x  U L  N,  > 5 x  U L  N, 
> 1 0 x  U L  N, t ot al  bilir u bi n  b y  > 1. 5 x  U L  N  a n d  > 2 x  U L  N.  
N u  m b er  of s u bj e cts   w h o   m e et   H y’s  L a  w  crit eri a (t ot al   Bilir u bi n    > = 2 x  U L  N  a n d   A L T  or   A S T 
> = 3 x  U L  N)   will  b e s u  m  m ari z e d  a n d  c orr es p o n di n g listi n g   will  b e  pr es e nt e d. 
N u  m b er  of  S u bj e cts   wit h  L y  m p h o p e ni a  b y   M a xi  m u  m   N  CI-  C T  C  A E  T o xi cit y   Gr a d e    1- 4 will  b e 
s u  m  m ari z e d.  S u bj e cts   wit h  L y  m p h o p e ni a  T o xi cit y   Gr a d e  2 or  hi g h er   will  als o  b e list e d.  
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2 7  of  3 7  
 
3. 7. 5.    
Vit al  Si g ns  a n d   E  C  G 
3. 7. 5. 1.    Vit al   Si g ns  
Vit al si g ns f or  e a c h  visit  d uri n g t h e  e ntir e st u d y   will  b e s u  m  m ari z e d  b y tr e at  m e nt    gr o u p  a n d 
o v er all.   All  vit al si g n  d at a   will  b e  pr es e nt e d i n t h e s u bj e ct  d at a listi n gs.  
N u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h  vit al si g n  v al u es  c o nsi d er e d  P  C S  o c c urri n g  at  a n y  p ost-
b as eli n e  visit   will  b e s u  m  m ari z e d  b y  tr e at  m e nt  gr o u p  a n d  o v er all.   Crit eri a f or  P  C S  ar e  pr es e nt e d 
i n T a bl e   3  a n d   will  b e  pr es e nt e d f or  e a c h p ar a  m et er.  T h e  p er c e nt a g es   will  b e  c al c ul at e d r el ati v e 
t o t h e  n u  m b er  of s u bj e cts   wit h  n o n-P  C S  b as eli n e  v al u es   wit h r es p e ct t o t h e s p e cifi c  crit eri o n  a n d 
at l e ast  1  p ost -b as eli n e  ass ess  m e nt.   A s u p p orti v e listi n g   will  pr es e nt  all  v al u es f or  a  p ar a  m et er f or 
s u bj e cts   wit h  at l e ast  o n e  P  C S  v al u e f or t h at  p ar a  m et er.  
I n  a d diti o n, t h e fi g ur e  of   m e a n  c h a n g e fr o  m  b as eli n e  al o n g   wit h t h e  c orr es p o n di n g  S E   will  b e 
su  m  m ari z e d  b y  visit  a n d  tr e at  m e nt  gr o u p a n d  o v er all  f or s yst oli c  bl o o d  pr ess ur e,  di ast oli c  bl o o d 
pr ess ur e,  a n d  h e art r at e.  
T a bl e  3:   
P ot e nti all y   Cli ni c all y  Si g nifi c a nt ( P  C S)  C rit e ri a f o r   Vit al  Si g ns 
P a r a  m et e r  
C rit e ri a   
S yst oli c   Bl o o d  Pr ess ur e  
L o  w:  ≤ 9 0   m  m   H g  a n d  d e cr e as e  ≥ 2 0   m  m   H g  
Hi g h:  ≥ 1 8 0   m  m   H g  a n d i n cr e as e  ≥ 2 0   m  m   H g 
Di ast oli c   Bl o o d  Pr ess ur e 
L o  w:  ≤ 5 0   m  m   H g  a n d  d e cr e as e  ≥ 1 5   m  m   H g  
Hi g h:  ≥ 1 0 5   m  m   H g  a n d i n cr e as e  ≥ 1 5   m  m   H g 
P uls e  R at e   
L o  w:  ≤ 5 0   m  m  b p  m  a n d  d e cr e as e  ≥ 1 5  b p  m 
Hi g h:   ≥ 1 2 0   m  m  b p  m  a n d i n cr e as e  ≥ 1 5  b p  m  
3. 7. 5. 2.    El e ct r o c a r di o g r a  ms   
E  C  G  p ar a  m et ers ( h e art r at e,   R  R i nt er v al,  P  R i nt er v al,   Q  R S i nt er v al,   Q T i nt er v al,   Q T c  B [  Q T 
i nt er v al  c orr e ct e d  usi n g   B a z ett’s   m et h o d],   Q T c F [  Q T i nt er v al  c orr e ct e d  usi n g  Fri d eri ci a's 
m et h o d])   will  b e s u  m  m ari z e d f or  e a c h  visit  d uri n g t h e   st u d y  b y tr e at  m e nt  gr o u p  a n d  o v er all.  
N u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h   Q T c F  p ar a  m et er  v al u es  c o nsi d er e d  P  C S  o c c urri n g  at 
a n y  p ost- b as eli n e  visit   will  b e s u  m  m ari z e d  b y  tr e at  m e nt  gr o u p  a n d  o v er all.   Crit eri a f or  P  C S  ar e 
pr es e nt e d i n  T a bl e   4  a n d   will  b e  pr es e nt e d f or  e a c h p ar a  m et er .   A s u bj e ct   will  b e  c o u nt e d  o nl y 
o n c e i n t h e  hi g h est  c at e g or y f or  a  gi v e n  p ar a  m et er  b as e d  o n t h e l ar g est  p ost- b as eli n e  v al u e.  T h e 
p er c e nt a g es   will  b e  c al c ul at e d r el ati v e t o t h e  n u  m b er  of s u bj e cts   wit h  b as eli n e  v al u e  ≤  4 5 0   ms e c 
a n d  at l e ast  1  p ost- b as eli n e  ass ess  m e nt i n t h e s af et y  a n al ysis s et .  
A s u p p orti v e listi n g   will  pr es e nt  all  v al u es f or  a  p ar a  m et er f or s u bj e cts   wit h  at l e ast  o n e  P  C S 
v al u e f or t h at  p ar a  m et er.  
T a bl e  4:   
P ot e nti all y   Cli ni c all y  Si g nifi c a nt ( P  C S)   C rit e ri a f o r   Q  T c F  
P a r a  m et e r  
C rit e ri a   
Q T c F   
> 4 5 0 t o  ≤ 4 8 0   ms e c 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2 8  of  3 7  
 
P a r a  m et e r  
C rit e ri a   
> 4 8 0 t o  ≤ 5 0 0   ms e c 
> 5 0 0   ms e c 
C h a n g e fr o  m  b as eli n e  > 3 0 t o  ≤ 6 0   ms e c 
C h a n g e fr o  m  b as eli n e  >  6 0   ms e c  
 
3. 7. 6.    
C ol u  m bi a  S ui ci d e  S e v e rit y   R ati n g  S c al e (  C  -S S  R S)  
T h e   C - S S  R S is  a  q u esti o n n air e  us e d t o   m e as ur e t h e  pr es e n c e  a n d i nt e nsit y  of s ui ci d al i d e ati o n 
a n d  b e h a vi or.  S ui ci d al  b e h a vi or  a n d s ui ci d al i d e ati o n   will  b e s u  m  m ari z e d  b y  tr e at  m e nt  gr o u p  a n d 
o v er all.  T h e  pr o p orti o n  of s u bj e cts   w h o   m e et t h e  crit eri o n f or  e a c h  of t h es e  c at e g ori es   will  b e 
s u  m  m ari z e d  as  d es cri b e d i n  T a bl e   5 . 
T a bl e  5:     
C- S S  R S   C at e g o ri es f o r   A n al ysis 
C at e g o r y 
C-  S S  R S It e  m  r es p o ns e is  “  Y  E S ”  
S ui ci d al  b e h a vi or   
Pr e p ar at or y  a cts  or  b e h a vi or  
A b ort e d  att e  m pt 
I nt err u pt e d  att e  m pt 
A ct u al  att e  m pt   
C o  m pl et e s ui ci d e   
S ui ci d al i d e ati o n    
Wis h t o  b e   d e a d  
N o n  -s p e cifi c  a cti v e s ui ci d al t h o u g hts 
A cti v e s ui ci d al i d e ati o n   wit h  a n y   m et h o ds ( n ot  pl a n)   wit h o ut i nt e nt t o  a ct   
A cti v e s ui ci d al i d e ati o n   wit h s o  m e i nt e nt t o  a ct,   wit h o ut s p e cifi c  pl a n   
A cti v e s ui ci d al i d e ati o n   wit h s p e cifi c  pl a n  a n d i nt e nt   
N o n  -S ui ci d al  S elf -
I nj uri o us   B e h a vi or 
N o n  -S ui ci d al  S elf -I nj uri o us   B e h a vi or 
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  2 9  of  3 7  
 
4.    
I  N  T  E  RI  M   A  NA  L  Y S  E S   A  N  D   D  A  T  A   M  O  NI  T  O  RI  N  G   C  O  M  MI  T  T  E  E 
(  D  M  C) 
N o i nt eri  m  a n al ysis   w as  pl a n n e d f or t his st u d y. 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3 0  of  3 7  
 
5.    
C  H  A  N  G  E S I  N   C  O  N  D  U  C  T   O  R  P  L  A  N  N  E  D   A  N  A  L  Y S  E S  F  R  O  M 
T  H  E  P  R  O  T  O  C  O  L   
N o n e. 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3 1  of  3 7  
 
6.    
D  E FI  NI  TI  O  N S   A  N  D   C  O  N  V  E  N  TI  O  N S  F  O  R   H  A  N  D  LI  N  G   O F   T  H  E 
D  A  T  A   
D at as et s p e cifi c ati o ns   will  b e  pr o vi d e d i n  a s e p ar at e  d o c u  m e nt. 
6. 1.    
A n al ysis   Visit   Wi n d o  ws   
S c h e d ul e d   a n al ysis   visits   ar e  visits   u p o n  s c h e d ul e d  ti  m e  p oi nts  as   s p e cifi e d  i n T a bl e   1 
S c h e d ul e  of   Visits  a n d  Ass ess  m e nt  s. 
S c h e d ul e d  a n al ysis  visits  d uri n g t h e st u d y  p eri o d   will  b e t h e s a  m e  as t h e  n o  mi n al   visits  c oll e ct e d  
i n t h e  e C R F.  T h er e  will    b e  o n e v ali d   v al u e  of t h e ass ess  m e nt   k e pt  f or e a c h  s c h e d ul e d  a n al ysis 
visit i n s u  m  m ar y/  a n al ysis  st atisti cs. 
U ns c h e d ul e d  visits  ar e  visits   wit h  d at a  n ot  c oll e ct e d  o n t h e s c h e d ul e d ti  m e  p oi nt.   U ns c h e d ul e d 
visits  will    n ot  b e us e d  f or b y -visit  s u  m  m ar y/ a n al ysis  st atisti cs  u nl ess s p e cifi e d  ot h er  wis e.  All 
u ns c h e d ul e d  visits   will  b e i n cl u d e d  as  c oll e ct e d i n  e  C  R F i n  listi n gs. 
6. 2.    
H a n dli n g  of  P a rti al   D at es  of   C o n c o  mit a nt   M e di c ati o n    
P arti al st art  d at es  of  pri or  a n d  c o n c o  mit a nt   m e di c ati o ns   will  b e  ass u  m e d t o  b e t h e  e arli est 
p ossi bl e  d at e  c o nsist e nt   wit h t h e  p arti al  d at e.  P arti al st o p  d at es  of  pri or  a n d  c o n c o  mit a nt 
m e di c ati o ns   will  b e  ass u  m e d t o  b e t h e l at est  p ossi bl e  d at e  c o nsist e nt   wit h t h e  p arti al  d at e. I n t h e 
c as e  of  c o  m pl et el y   missi n g st o p  d at es,   m e di c ati o n   will  b e  ass u  m e d t o  b e  o n g oi n g.  
6. 3.    
S af et y   D at a   H a n dli n g   
All  eff orts s h o ul d  b e   m a d e t o  o bt ai n t h e   missi n g i nf or  m ati o n fr o  m   t h e I n v esti g at or.  F or   C-S S  R S, 
vit al si g ns, l a b or at or y t esti n g ( c h e  mistr y,  h e  m at ol o g y,  uri n al ysis),  a n d  1 2-l e a d  E  C  Gs,  o nl y 
o bs er v e d  d at a   will  b e  us e d f or  a n al ys es,  a n d   missi n g  d at a   will  n ot  b e i  m p ut e d. 
 
 
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3 2  of  3 7  
 
7.    
G  E  N  E  R  A  L  S  T  A  TI S  TI  C  A  L   M  E  T  H  O  D  O  L  O  G  Y 
I n  g e n er al, s u  m  m ar y st atisti cs ( n,   m e a n,  S  D,   m e di a n,   mi ni  m u  m,  a n d   m a xi  m u  m f or  c o nti n u o us 
v ari a bl es,  a n d  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts i n  e a c h  c at e g or y f or  c at e g ori c al  v ari a bl es)   will 
b e  pr o vi d e d  b y tr e at  m e nt  gr o u p.   All s u  m  m ar y t a bl es   will  b e  b as e d  o n  o bs er v e d  d at a,  a n d   m issi n g 
v al u es   will  n ot  b e i  m p ut e d  u nl ess  ot h er  wis e i n di c at e d.   M e as ur e  m e nts  c oll e ct e d fr o  m 
u ns c h e d ul e d  visits  or r e p e at e d  ass ess  m e nts   will  n ot  b e i n cl u d e d i n t h e  b y- visit s u  m  m ar y t a bl es  or 
fi g ur es,  b ut   will  b e i n cl u d e d i n t h e  d eri v ati o n  of t h e l ast  p ost-b as eli n e  v al u e  d uri n g tr e at  m e nt, t h e 
a n al ys es  of  P  C S  p ost- b as eli n e  v al u es,  a n d s u bj e ct listi n g s.  S o ur c e  d at a f or t h e s u  m  m ar y t a bl es 
a n d st atisti c al  a n al ys es   will  b e  pr es e nt e d  as s u bj e ct  d at a listi n gs.  
7. 1.    
R e p o rti n g  P r e cisi o n   
S u  m  m ar y st atisti cs   will  b e  pr es e nt e d t o t h e  d e gr e e  of  pr e cisi o n i n  T a bl e   6,  u nl ess  ot h er  wis e 
s p e cifi e d:  
T a bl e  6:   
D e g r e e  of  P r e cisi o n   
St atisti cs  
D e g r e e  of  P r e cisi o n   
M e a n,   G e o  m etri c   m e a n,   M e di a n,   Q u artil es, 
C o nfi d e n c e li  mit  b o u n d ari es 
O n e   m or e t h a n t h e r a  w  d at a,  u p t o  3  d e ci  m al  pl a c es. 
St a n d ar d  d e vi ati o n,  St a n d ar d  err or   
O n e   m or e t h a n t h e   m e a n,  u p t o  3  d e ci  m al  pl a c es 
Mi ni  m u  m,   M a xi  m u  m   
T h e s a  m e  as t h e r a  w  d at a,  u p t o  2  d e ci  m al  pl a c es  
p- v al u e  
R o u n d e d t o  3  d e ci  m al  pl a c es  a n d t h er ef or e  pr es e nt  e d  as 
0. x x x;  p - v al u es s  m all er t h a n  0. 0 0 1  as ‘ < 0. 0 0 1’;  p-v al u es 
gr e at er t h a n  0. 9 9 9  as ‘ > 0. 9 9 9’. 
P er c e nt a g e  
O n e  d e ci  m al  pl a c e.   A  p er c e nt a g e  of  1 0 0  %   will  b e r e p ort e d 
as  1 0 0  %.  P er c e nt a g es  of  z er o   will  b e r e p ort e d  as  0.  
Fr a cti o n al  n u  m eri c  v al u es   will  b e  pr es e nt e d   wit h  a  z er o t o t h e l eft  of t h e  d e ci  m al  p oi nt (f or 
e x a  m pl e,  0. 1 2 – 0. 3 0). 
F or   w ei g ht,  h ei g ht,  a n d  b o d y   m ass i n d e x (  B  MI),  o n e  d e ci  m al  pl a c e   will  b e  us e d f or s u  m  m ar y 
st atisti cs. 
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3 3  of  3 7  
 
8.    
P  R  O  G  R  A  M  MI  N  G  S P  E  CI FI  C A  TI  O  N S   
Pr o gr a  m  mi n g s p e cifi c ati o ns   will  b e  pr o vi d e d i n  a s e p ar at e  d o c u  m e nt.  


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3 4  of  3 7  
 
9.    
M  O  C  K   T  A  B  L  E S,   LI S  TI  N  G S   A  N  D   G  R  A P  H S (  T  L  G S)   
M o c k  - u p t a bl es  a n d listi n gs   will  b e  pr o vi d e d i n  a s e p ar at e  d o c u  m e nt. 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3 5  of  3 7  
 
1 0.    
R  E F  E  R  E  N  C  E S   
1.    Al k er  m es   A L  K 8 7 0 0-  A 3 0 2   Cli ni c al  St u d  y  Pr ot o c ol   A  m e n d  m e nt : 1 5 D E  C   2 0 1 6 
2.    Al k er  m es   A L  K 8 7 0 0-  A 3 0 2   Cli ni c al  St u d y  Pr ot o c ol   A  m e n d  m e nt  1. 1 f or sit es i n  P ol a n d 
o nl y:  2 3   A u g  2 0 1 7 
3.    Al k er  m es   A L  K 8 7 0 0-  A 3 0 2   Cli ni c al  St u d y  Pr ot o c ol   A  m e n d  m e nt  2. 0 (i n c or p or at e d 
A d  mi nistr ati v e   C h a n g e   M e  m o  1):  2 0  S e p  2 0 1 8 
4.    Al k er  m es   A L  K 8 7 0 0-  A 3 0 2   Cli ni c al  St u d y  Pr ot o c ol   G er  m a n y  -s p e cifi c   A  m e n d  m e nt  2. 2 
(i n c or p or at e d   A d  mi nistr ati v e   C h a n g e   M e  m o  2):  1 4   D e c  2 0 1 8 
 
 
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3 6  of  3 7  
 
A P P  E  N  DI  X I   A  L  K 8 7 0 0  -A 3 0 2  P  A  R  T   A  S  A P   
 
 


Al k er  m es, I n c.                                                                                                                              A L  K 8 7 0 0  -A 3 0 2    
C  O  N FI  D E  N TI  A L   
St atisti c al   A n al ysis  Pl a n  
 
P a g e  3 7  of  3 7  
 
A P P  E  N  DI  X I  I A  E SI   S  E  A  R  C  H   C  RI  T  E  RI  A