Clinical trial NCT04413552
Conditions: Opioid Dependence
Sponsor: Indivior Inc.
Start date: 2020-07-06; Completion date: 2021-04-13
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is a single ascending dose (SAD) study conducted to identify the maximum tolerated dose (MTD) of INDV-2000. After completion of the SAD portion of the study and acceptable safety evaluation, a food-interaction, single-dose study under fed and fasted conditions will be conducted.

Detailed description:

Arms: arm 1: Participants will receive a single dose of INDV-2000. The starting dose is 1 mg with dose escalation dependent upon observed clinical safety, tolerability and pharmacokinetics. arm 2: Participants will receive a single dose of matching placebo. arm 3: Participants will receive a single dose of INDV-2000 orally on Day 1 under fasted conditions and a single dose of INDV-2000 after a high-fat breakfast on Day 8. Dose to be determined based on a well-tolerated dose studied in Part I.
Interventions: intervention 1: INDV-2000 intervention 2: Placebo
Intervention descriptions: intervention 1: INDV-2000 will be administered as either powder in solution or powder in capsule, depending on dose administered. intervention 2: Placebo will be administered as either powder in solution or powder in capsule, depending on dose administered.

Protocol documents:
ICF_000.pdf: 
Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  1  of  1 5  
 
S U B J E C T I N F O R M A TI O N  A N D  C O N S E N T  F O R M  
A N D  
A U T H O RI Z A TI O N  F O R  R E L E A S E  O F  P R O T E C T E D  H E A L T H I N F O R M A TI O N  
 
T I T L E 
 
 
 
 
A   
P h as e   
I,    
D o u bl e -bli n d,   
Pl a c e b o -c o ntr oll e d, 
R a n d o mi z e d,  Si n gl e  As c e n di n g  D os e  St u d y t o  Ass ess 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  of  I N D V - 2 0 0 0 
( C 4 X _ 3 2 5 6)  u n d er  F asti n g  a n d  F e d  C o n diti o ns i n  H e alt h y 
V ol u nt e ers 
 
P R O T O C O L  N O.  
 
I N D V-2 0 0 0 -1 0 1  
P art  1  
P RI N CI P A L I N V E S TI G A T O R 
(S T U D Y  D O C T O R ) 
 
,  M. D.,  P h D,  M P H 
 
R E S E A R C H  SI T E  A D D R E S S  
Alt as ci e n c es  Cli ni c al  K a ns as , I n c. 
1 0 1 0 3  a n d/ or  1 0 2 0 3  a n d/ or  1 0 1 8 3  M et c alf  A v e n u e  
O v erl a n d  P ar k,  K S   6 6 2 1 2 
 
T E L E P H O N E  N U M B E R  
( 9 1 3)  6 9 6-1 6 0 1 ( 2 4 -h o ur  n u m b er)  
 
S P O N S O R  
I n di vi or 
K E Y I N F O R M A TI O N  O N  T H E  S T U D Y  
•   D uri n g  t h e   st u d y   y o u    will   r e c ei v e   a   si n gl e  or al   d os e   of   eit h er  t h e  i n v esti g ati o n al   dr u g 
(I N D V- 2 0 0 0)  t h at  is  b ei n g  d e v el o p e d  f or  t h e  p ot e nti al  tr e at m e nt  of  o pi oi d  us e  dis or d er  or  a 
pl a c e b o ( d u m m y s u bst a n c e t h at l o o ks li k e t h e i n v esti g ati o n al  dr u g  wit h o ut  a n y  a cti v e  dr u g).  
•   T his is  t h e fi rst  st u d y i n  w hi c h  I N D V-2 0 0 0 is  b ei n g t est e d i n  h u m a ns.  It  h as  b e e n t est e d i n 
a ni m als.  
•   T hr o u g h o ut t h e st u d y, t h e f oll o wi n g  pr o c e d ur es  will  b e  d o n e t o  e ns ur e  y o ur s af et y: 
o   P h ysi c al  e x a m  
o   El e ctr o c ar di o gr a m ( E C G)  - a t est t o  m o nit or t h e  el e ctri c al  a cti vit y  of  y o ur  h e art  
o   Vit al si g ns  
o   L a b or at or y t ests ( bl o o d  a n d  uri n e  s a m pl es will  b e t a k e n)  
o   M o nit ori n g  b y t h e st u d y st aff 
o   C o nfi n e m e nt  at t h e r es e ar c h sit e f or  4  ni g hts  ( D a ys - 1 t o  D a y  4) 
o   F oll o w- u p  visit  o n  D a y  1 1 
•   T hr o u g h o ut  t h e  st u d y,  t h e  f oll o wi n g  pr o c e d ur es   will  b e  d o n e  t o  l e ar n  a b o ut  t h e  eff e cts  of  t h e 
st u d y  dr u g: 
o   S e d ati o n  Vis u al  A n al o g  S c al e ( V A S )  – A n  ass ess m e nt t h at  will  m e as ur e  y o ur l e v el  of 
sl e e pi n ess  
o   Bl o o d  a n d  uri n e s a m pl e  c oll e cti o n t o  m e as ur e st u d y  dr u g l e v els 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  2  of  1 5  
 
P U R P O S E  O F  T H E  S U B J E C T I N F O R M A TI O N  A N D  C O N S E N T  F O R M  
T his  S u bj e ct  I nf or m ati o n  a n d  C o ns e nt  F or m  m a y  c o nt ai n  w or ds  or  pr o c e d ur es  y o u  d o  n ot  u n d erst a n d. 
Pl e as e  as k t h e st u d y st aff  t o  e x pl ai n  a n y  w or ds  or  pr o c e d ur es t h at  y o u  d o  n ot  u n d erst a n d. 
T h e  p ur p os e  of t his  f or m is t o  gi v e  y o u i nf or m ati o n  a b o ut t his  r es e ar c h  st u d y.  T his  f or m  d es cri b es t h e 
p ur p os e,  pr o c e d ur es,  b e n efits,  ris ks,  dis c o mf orts,  a n d  pr e c a uti o ns  of  t his  r es e ar c h  st u d y.    Y o u  s h o ul d 
o nl y t a k e  p art i n t h e  st u d y if  y o u  w a nt t o  d o  s o.  Y o u  m a y  r ef us e t o t a k e  p art i n t his  st u d y , or  y o u  m a y 
c h o os e t o  wit h dr a w  fr o m t his  st u d y , at  a n y ti m e , wit h o ut  a  p e n alt y  or l oss  of t h e  b e n efits t o  w hi c h  y o u 
ar e  ot h er wis e  e ntitl e d.  Pl e as e r e a d t his  S u bj e ct I nf or m ati o n  a n d  C o ns e nt  F or m,  as k  as  m a n y  q u esti o ns  as 
n e e d e d,  a n d  d o  n ot  si g n t his f or m if  y o u  h a v e  a n y  q u esti o ns t h at  h a v e  n ot  b e e n  a ns w er e d t o  y o ur li ki n g. 
O n c e  y o u  h a v e r e a d t his  d o c u m e nt, if  y o u  a gr e e t o t a k e  p art,  y o u  will  b e  as k e d t o  si g n t h e  c o ns e nt f or m. 
B y  si g ni n g t his  d o c u m e nt,  y o u  ar e  st ati n g t h at  y o u  h a v e  b e e n  f ull y i nf or m e d  a n d  gi v e  y o ur  c o ns e nt  t o 
t a k e  p art i n t h e st u d y. 
A  c o p y  of t his  si g n e d  a n d  d at e d  c o ns e nt f or m  will  b e  gi v e n t o  y o u t o  k e e p.  B e  s ur e t o t a k e t h e ti m e t o 
r e a d t hr o u g h t his i nf or m ati o n  c ar ef ull y t o  d e ci d e if  y o u  w o ul d li k e t o t a k e  p art i n t his st u d y. 
D E S C RI P TI O N  A N D  P U R P O S E  O F  T H E  S T U D Y  
T h e  n a m e  of t h e i n v esti g ati o n al  dr u g t h at  y o u  will  r e c ei v e  i n t his  st u d y is I N D V- 2 0 0 0.  I N D V- 2 0 0 0  is 
b ei n g  d e v el o p e d  f or  t h e p ot e nti al tr e at m e nt  of  o pi oi d  us e  dis or d er . I n v esti g ati o n al  m e a ns t h at t h e  dr u g 
h as  n ot  b e e n  a p pr o v e d  b y t h e  U. S.  F o o d  a n d  Dr u g  A d mi nistr ati o n  ( F D A).  Y o u  m a y  b e  gi v e n  pl a c e b o 
( d u m m y  s u bst a n c e  t h at  l o o ks  li k e  I N D V- 2 0 0 0    wit h o ut  a n y  a cti v e  dr u g)  i nst e a d  of  I N D V- 2 0 0 0.  T h e 
d os a g e  will  b e i n  c a ps ul e  or  s ol uti o n (li q ui d)  f or m d e p e n di n g  o n t h e  a m o u nt  b ei n g  a d mi nist er e d  a n d  w ill 
b e t a k e n  or all y ( b y  m o ut h). 
T h e  i nt e nt of t his  r es e ar c h  st u d y is  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 
si n gl e,  es c al ati n g  or al  d os e  of  I N D V- 2 0 0 0 i n  h e alt h y a d ult  s u bj e cts. P h ar m a c o ki n eti cs ( P K) is t h e  st u d y 
of  h o w  a  dr u g  is  a bs or b e d,  distri b ut e d,    m et a b oli z e d,  a n d  e v e nt u all y  eli mi n at e d  b y  t h e  b o d y.    Bl o o d 
s a m pl es  will  b e  dr a w n  t hr o u g h o ut t h e  st u d y f or  P K  a n al ysis. A n ot h er i nt e nt  of t his r es e ar c h  st u d y is t o 
d et er mi n e t h e  m a xi m u m t ol er at e d  d os a g e  a n d t h e  eff e cts  of  a  hi g h -f at m e al  o n t h e  P K  of I N D V - 2 0 0 0.  
T h er e  ar e t w o  p arts t o t his  st u d y.  Y o u  c a n  o nl y  p arti ci p at e i n  o n e  p art.  T his is t h e  s u bj e ct i nf o r m ati o n 
a n d  c o ns e nt f o r m f o r  P a rt  1.   
It is i m p ort a nt t h at  y o u  u n d erst a n d  h o w  oft e n  y o u  will  n e e d t o  c o m e t o t h e  r es e ar c h  sit e  f or t h e  visits, 
h o w l o n g t h e i n -h o us e  st a y is,  a n d t h at  y o u  ar e  a bl e t o  k e e p t o t h e  st u d y  s c h e d ul e  a n d f oll o w t h e r ul es  of 
t h e r es e ar c h sit e. 
T h e  d ur ati o n  of  y o ur  p arti ci p ati o n i n t his  st u d y  will  b e  a p pr o xi m at el y  3 9  d a ys i n cl u di n g t h e  s cr e e ni n g 
visit.  S cr e e ni n g  will  o c c ur  wit hi n  2 8  d a ys  pri or t o  y o u t a ki n g t h e st u d y  dr u g. 
If  y o u  q u alif y  a n d  d e ci d e t o  p arti ci p at e,  y o u  will  b e  o n e  of  a p pr o xi m at el y 4 8  h e alt h y,  n o n -s m o ki n g,  n o n-
t o b a c c o  usi n g,  a d ult   m al e a n d  n o n- c hil d b e ari n g  p ot e nti al  f e m al e  s u bj e cts,  b et w e e n  t he  a g es  of  1 8  a n d 
5 5 , i n cl usi v e, p arti ci p ati n g i n t his  p art  of t h e  r es e ar c h st u d y.  T h e t ot al  n u m b er  of  p arti ci p a nts  f or  b ot h 
p arts  of t his r es e ar c h  st u d y is  5 6  p e o pl e.  A d diti o n al  s u bj e cts i n  e a c h  gr o u p  m a y  als o  b e  a d mitt e d t o t h e 
r es e ar c h sit e t h e  d a y  b ef ore  d osi n g f or  e a c h  gr o u p  a n d  m a y s er v e  as  b a c k -u p st u d y  s u bj e cts.  Y o u  m a y  b e 
s el e ct e d t o  p arti ci p at e i n t his r es e ar c h st u d y  as  eit h er  a st u d y s u bj e ct  or  a  b a c k - u p st u d y s u bj e ct. 
T h is is t h e  o nl y r es e ar c h sit e p arti ci p ati n g i n t his st u d y.  


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  3  of  1 5  
 
D O SI N G  A N D  P R O C E D U R E S  
T his is  a  “ d o u bl e- bli n d ”  st u d y .  T his m e a ns t h at  n eit h er  y o u ,  n or st u d y  st aff, will  k n o w if  y o u  ar e t a ki n g 
I N D V- 2 0 0 0  or  pl a c e b o.    D uri n g  t h e  st u d y,  y o u    will  b e  assi g n e d  t o  r e c ei v e  I N D V- 2 0 0 0  or  pl a c e b o  
r a n d o ml y  ( b y  c h a n c e,  li k e  fli p pi n g  a  c oi n). T h e  p h ar m a c y  st aff  at  t h e  r es e ar c h  sit e  will  k n o w    w hi c h 
st u d y  dr u g  will  b e  a d mi nist er e d t o  y o u . I n  a n  e m er g e n c y, t h e  st u d y st aff c a n  fi n d  o ut  if  y o u  h a v e  b e e n 
gi v e n  I N D V- 2 0 0 0 if it is  n e c ess ar y f or  y o ur  m e di c al  c ar e.  
Y o u  will  p arti ci p at e i n  1  of  6  p ossi bl e  d os e  gr o u ps. I n  e a c h  d os e  gr o u p, s u bj e cts  will  b e  di vi d e d i nt o t w o 
s u b gr o u ps,  f or  s af et y  p ur p os es.   T h e  first  s u b gr o u p   will  i n cl u d e t w o  s u bj e cts.   O n e  s u bj e ct   will  r e c ei v e 
I N D V-2 0 0 0  a n d  o n e  s u bj e ct    will  r e c ei v e  pl a c e b o .  A  s af et y  r e vi e w  of  d at a  c oll e ct e d  fr o m  t h e  first 
s u b gr o u p  will  b e  d o n e t o  e ns ur e t h at it is  s af e t o  c o nti n u e  wit h t h e  s e c o n d  s u b gr o u p.  At l e ast  o n e  d a y 
aft er, t h e  s e c o n d  s u b gr o u p , m a d e  u p  of  t h e si x  r e m ai ni n g  s u bj e cts, will  r e c ei v e t h e  st u d y  dr u g  (I N D V -
2 0 0 0  or  pl a c e b o). I n t ot al,  si x  s u bj e cts  will  b e  gi v e n I N D V -2 0 0 0  a n d  2  s u bj e cts  will  b e  gi v e n  pl a c e b o i n 
e a c h  d os e  gr o u p. 
If  y o u  ar e  s el e ct e d  t o  b e  p art  of  t h e  first  s u b gr o u p,  y o u  h a v e  a  1  i n  2  ( 5 0 %)  c h a n c e  of  r e c ei vi n g 
I N D V-2 0 0 0.  If  y o u  ar e  s el e ct e d t o  b e  p art  of t h e  s e c o n d  s u b gr o u p  y o u  h a v e  a  5 i n  6  ( 8 3 %)  c h a n c e  of 
r e c ei vi n g I N D V- 2 0 0 0. 
T h e  s af et y  r e vi e w  f or  t h e  first  s u b gr o u p of  e a c h  d os e  gr o u p  will  b e  p erf or m e d  b y  t h e  st u d y  st aff  a n d 
m e di c all y  q u alifi e d  p ers o n n el r e pr es e nti n g t h e  s p o ns or.  
Y o u  will  o nl y  b e  p arti ci p ati n g  i n  o n e  gr o u p.  T h e  pl a n n e d  d os es f or  gr o u ps  1- 6  ar e  pr o vi d e d  b el o w. 
G r o u p  
N o.  of 
S u bj e cts  
D os e  
C a ps ul e  o r 
S ol uti o n 
N u m b e r  of s u bj e cts 
r e c ei vi n g  
I N D V- 2 0 0 0 /  Pl a c e b o 
1 ( 1 st s u b gr o u p)   
2   
1  m g   
S ol uti o n  
1/ 1  
1 ( 2 n d s u b gr o u p)   
6   
1  m g   
S ol uti o n  
5/ 1  
2 ( 1 st s u b gr o u p)   
2   
5  m g   
S ol uti o n  
1/ 1  
2 ( 2 n d s u b gr o u p)   
6   
5  m g   
S ol uti o n  
5/ 1  
3 ( 1 st s u b gr o u p)   
2   
2 0  m g   
C a ps ul e  
1/ 1  
3 ( 2 n d s u b gr o u p)   
6   
2 0  m g   
C a ps ul e  
5/ 1  
4 ( 1 st s u b gr o u p)   
2   
5 0  m g   
C a ps ul e  
1/ 1  
4 ( 2 n d s u b gr o u p)   
6   
5 0  m g   
C a ps ul e  
5/ 1  
5 ( 1 st s u b gr o u p)   
2   
1 2 0  m g   
C a ps ul e  
1/ 1  
5 ( 2 n d s u b gr o u p)   
6   
1 2 0  m g   
C a ps ul e  
5/ 1  
6 ( 1 st s u b gr o u p)   
2   
2 0 0  m g   
C a ps ul e  
1/ 1  
6 ( 2 n d s u b gr o u p)   
6   
2 0 0  m g   
C a ps ul e  
5/ 1  
 
All  d os es  will  b e  gi v e n i n t h e f ast e d  st at e ( n o f o o d  or  dri n k  ot h er t h a n  w at er f or  a  mi ni m u m  of  1 0   h o urs) 
a n d  will  b e t a k e n  wit h  a p pr o xi m at el y  2 4 0  m L ( 8  o u n c es)  of  w at er.  
Y o u  will  o nl y r e c ei v e  o n e  d os e  of  I N D V- 2 0 0 0 or  pl a c e b o  i n t h e  m or ni n g  o n  D a y  1  of t h e st u d y. 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  4  of  1 5  
 
If  y o u  ar e i n  d os e  gr o u ps  2 t o  6,  or  a n y  a d diti o n al  d os e  gr o u p, t h e d e cisi o n t o i n cr e as e  y o ur  d os e l e v el 
will  b e    m a d e  b y  t h e  D at a   R e vi e w  a n d  S af et y   C o m mitt e e   aft er  t h e y  r e vi e w  all  l a b or at or y  t ests,  vit al 
si g ns,  E C G  d at a, r e p ort e d  si d e  eff e cts,  a n d  P K  d at a  fr o m  pr e vi o us  d os e  gr o u p(s). T his is t o  b e  s ur e t h e 
pri or  d os e  l e v el   w as   w ell -t ol er at e d. D e p e n di n g  o n t h e  o v er all  r es ults  of t his  r e vi e w,  t h e  d os e  f or  y o ur  
gr o u p  c o ul d  b e  hi g h er,  l o w er,  t h e  s a m e , or  t h e  st u d y  c o ul d  b e  st o p p e d . N o  d os e   will  b e  hi g h er  t h a n 
2 0 0  m g.  
A d diti o n al  d os e  gr o u ps  m a y  b e  e nr oll e d  at t h e  dis cr eti o n  of t h e s p o ns or. 
S c r e e ni n g  
B ef or e t h e  st u d y  st arts,  y o u  will  b e  as k e d t o  si g n t his  c o ns e nt f or m.  Y o u  will  b e  as k e d t o  gi v e  p ers o n al 
i nf or m ati o n  a b o ut  y o urs elf  s u c h  as  d at e  of  birt h,  r a c e,  et c.  Y o u  will  b e  as k e d  a b o ut  y o ur  m e di c al   a n d 
m e di c ati o n  hist or y.  Y o u  m ust  b e  h o n est  wit h t h e st u d y st aff  a b o ut  y o ur  h e alt h  a n d  m e di c ati o n  hist or y,  or 
it  m a y  n ot  b e  s af e f or  y o u t o  b e i n t his  st u d y. Y o u  will  b e  as k e d  a n d it is  v er y i m p ort a nt t h at  y o u  t ell t h e 
st u d y  st aff  if  y o u  t a k e  a n y  o v er -t h e-c o u nt er  or  pr es cri pti o n    m e di ci n es,  vit a mi ns ,  h er b al  pr o d u cts ,  or 
n utriti o n al  s u p pl e m e nts.  Y o u  will  als o  b e  as k e d  a b o ut  pri or  c aff ei n e,  al c o h ol, t o b a c c o,  illi cit  dr u g  a n d 
c o ntr oll e d  s u bst a n c e  us e.  A n y  p ositi v e t est r es ult f or  pr o hi bit e d  a n d illi cit  dr u gs  or  al c o h ol  at  s cr e e ni n g 
or  at  c h e c k i n  will  e x cl u d e  y o u fr o m  p arti ci p ati n g f urt h er i n t h e st u d y. 
T h e  st u d y  st aff  will  d o  s o m e  t ests  t o  fi n d  o ut  if  y o u  c a n  b e  i n  t h e  st u d y.    T h es e  t ests  i n cl u d e  t h e 
f oll o wi n g: 
•   C o m pl et e  p h ysi c al  e x a mi n ati o n   
•   Vit al si g ns ( bl o o d  pr ess ur e,  h e art r at e ,  br e at hi n g r at e,  a n d  or al  b o d y te m p er at ur e )  
•   H ei g ht  a n d  w ei g ht 
•   C al c ul at e  B o d y  M a ss I n d e x (B MI ) -  a  m e as ur e  of  y o ur  w ei g ht i n r el ati o n t o  y o ur  h ei g ht) 
•   Si n gl e  E C G  ( m al e  s u bj e cts  m a y  b e r e q uir e d t o  h a v e t h eir  c h est  s h a v e d f or t h e  E C G;  f e m al e  s u bj e cts 
m a y  n ot  b e  all o w e d t o  w e ar  a  br a  f or t h e  E C G) 
•   Bl o o d  a n d  uri n e s a m pl es f or l a b or at or y t ests 
•   Uri n e  dr u g s cr e e n * 
•   Bl o o d t est f 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 d  He p atitis  B  a n d  C * 
•   Bl o o d  p r e g n a n c y t est f or f e m al es* 
•   Bl o o d t est t o  c o nfir m  m e n o p a us al st at us f or f e m al e s u bj e cts 
•   Al c o h ol  uri n e t est * 
* T h es e t ests  m ust  b e  n e g ati v e i n  or d er t o  c o nti n u e i n t h e st u d y. 
Pri or t o t h e  a b o v e t ests,  y o u  will  n e e d t o f ast ( n o f o o d  or  dri n k  ot h er t h a n  w at er ) f or  at l e ast  8  h o urs. 
HI V  A nti b o d y  a n d  H e p atitis  T esti n g  
As  r e q uir e d  f or  p arti ci p ati o n  i n  t his  r ese ar c h  st u d y,  y o u   m ust  h a v e  y o ur  bl o o d  t est e d  f or  t h e  h e p atitis 
vir us es  a n d f or  HI V.  HI V is t h e  vir us t h at  c a us es  AI D S. If  y o u  h a v e  a  p ositi v e  HI V  or  h e p atitis t est,  y o u 
c a n n ot  b e  i n  t h e  st u d y.  It    m a y  t a k e   w e e ks  or    m o nt hs  aft er  b ei n g  i nf e ct e d   wit h   HI V  f or  th e  t est  t o  b e 
p ositi v e. 
If eit h er  of t h es e t ests  is  p ositi v e,  a c o nfir m ati o n t est  will  b e  d o n e  b y t h e l a b or at or y.  
If t h e  HI V or  h e p atitis  t est ar e  p ositi v e,  y o u  will  b e  n otifi e d  b y t h e  r es e ar c h  sit e  a n d  gi v e n i nf or m ati o n 
o n  h o w t o f oll o w -u p f or f urt h er  m e d i c al  c ar e. As r e q uir e d  b y l a w,  p ositi v e t est r es ults  m ust  b e r e p ort e d 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  5  of  1 5  
 
b y t h e r es e ar c h sit e  t o t h e  St at e  D e p art m e nt  of  H e alt h. If  y o u  h a v e  a n y  q u esti o ns  a b o ut  w h at i nf or m ati o n 
is r e q uir e d t o  b e r e p ort e d,  pl e as e  as k t h e st u d y st aff. 
Alt h o u g h t his t esti n g is  s u p p os e d t o  b e  pri v at e, t his  c a n n ot  b e  g u ar a nt e e d.  F or  e x a m pl e, it is  p ossi bl e f or 
a  c o urt  of l a w t o  g et  h e alt h  or st u d y r e c or ds  wit h o ut  y o ur  p er missi o n. 
S T U D Y  P R O C E D U R E S  
R es e a r c h  Sit e  A d missi o n  -  D a y - 1 
Y o u   will  r e p ort  t o  t h e  r es e ar c h  sit e. Y o u   will  b e  c o nfi n e d  t o  t h e  r es e ar c h  sit e f or  4  ni g hts.  St a n d ar d 
m e als  a n d  dri n ks  d uri n g  y o ur  st a y  will  b e  pr o vi d e d.  Y o u  will  e at  o nl y t h e  f o o d  a n d  dri n ks  pr o vi d e d  at 
t h e s c h e d ul e d  m e al ti m es. 
U p o n  a d missi o n t o t h e r es e ar c h  sit e, t h e f oll o wi n g  pr o c e d ur es  will t a k e  pl ac e : 
•   Bri ef  P h ysi c al  e x a mi n ati o n  
•   Si n gl e  E C G  
•   V it al si g ns ( bl o o d  pr ess ur e, h e art r at e ,  br e at hi n g r at e,  a n d  or al  b o d y t e m p er at ur e) will  b e t a k e n  
•   Bl o o d  a n d  uri n e s a m pl es f or l a b or at or y t ests 
•   Y o u  will  b e  as k e d  a b o ut  m e di c al  a n d  m e di c ati o n  hist or y  si n c e  y o ur  s cr e e ni n g  visit  or if  y o u  h a v e 
e x p eri e n c e d  a n y  c h a n g es i n  h e alt h si n c e   y o ur s cr e e ni n g  visit 
•   Uri n e  dr u g s cr e e n * 
•   Uri n e  pr e g n a n c y t est f or f e m al es *  
•   Al c o h ol  uri n e t est * 
•   S e d ati o n    Vis u al    A n al o g  S c al e  ( V A S)  tr ai ni n g  –  A n  ass ess m e nt  t h at    will    m e as ur e  y o ur  l e v el  of  
sl e e pi n ess  
* T h es e t ests  m ust  b e  n e g ati v e i n  or d er t o  c o nti n u e i n t h e st u d y. 
Aft er  c o m pl eti o n  of  t h es e  pr o c e d ur es, it will  b e  d et er mi n e d  b y t h e  st u d y st aff if y o u  m a y  c o nti n u e i n t h e 
st u d y.  
Y o u    will  b e gi n  f asti n g  ( n o  f o o d   or  dri n k  ot h er  t h a n    w at er )  i n  t h e  e v e ni n g  t o  e ns ur e  a    mi ni m u m  of 
1 0  h o urs  wit h o ut f o o d  b ef or e  d osi n g. 
D a y  1 
B ef or e  y o u r e c ei v e t h e st u d y  dr u g ( I N D V- 2 0 0 0  or  pl a c e b o), t h e f oll o wi n g  pr o c e d ur es  will t a k e  pl a c e: 
•   C o nti n u o us  E C G  r e c or di n g  usi n g  a  H olt er  m o nit or  will  b e  p erf or m e d  fr o m  at l e ast  2  h o urs  pri or t o 
d osi n g  wit h t h e  st u d y  dr u g  u ntil  2 4  h o urs  aft er  d osi n g  ( a p pr o xi m at el y  2 6  h o urs).  A  H olt er  m o nit or 
us es  el e ctr o d es  a n d  a r e c or di n g  d e vi c e t o tr a c k  y o ur  h e art’s r h yt h m.  Y o u  will  n ot  b e  all o w e d t o t a k e 
a s h o w er  d uri n g t his  2 6- h o ur  m o nit ori n g ti m e . 
•   Vit al  si g ns ( bl o o d  pr ess ur e, h e art r at e ,  br e at hi n g r at e,  a n d  or al  b o d y t e m p er at ur e) r e c or d e d  3 ti m es 
•   Si n gl e  E C G  r e c or d e d  3 ti m es 
•   Bl o o d s a m pl e  f or  P K  a n al ysis 
•   Uri n e s a m pl e  f or  P K  a n al ysis 
•   S e d ati o n  V A S  
•   BI T R E X  s ol uti o n  ( us e d  t o   m as k  a n y  bitt er  t ast e  diff er e n c es  b et w e e n  I N D V -2 0 0 0  a n d  pl a c e b o) , t o 
ri ns e t h e  m o ut h f or  3 0 s e c o n ds,  5  mi n ut es  b ef or e  d osi n g ( F or  d os e  gr o u ps  1  a n d  2  o nl y) 
•   Y o u  will  b e  as k e d  h o w  y o u  ar e f e eli n g   a n d if  y o u  h a v e t a k e n  a n y  m e di c ati o ns 
St u d y  dr u g  will t h e n  b e  a d mi nist er e d  wit h  a p pr o xi m at el y   2 4 0  m L ( 8  o u n c es) of  w at er.  


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  6  of  1 5  
 
Aft er r e c ei vi n g t h e st u d y  dr u g, t h e f oll o wi n g  pr o c e d ur es  will  t a k e  pl a c e: 
•   Vit al  si g ns  ( bl o o d  pr ess ur e,  h e art  r at e ,  br e at hi n g  r at e,  a n d  or al  b o d y  t e m p er at ur e )  will  b e  t a k e n 
a p pr o xi m at el y  1,  2,  3,  4,  8,  a n d  1 2  h o urs  aft er  d osi n g 
•   Si n gl e  E C G   will  b e  d o n e  a p pr o xi m at el y  1,  2,  3,  4,  8,  a n d  1 2  h o urs  aft er  d osi n g 
•   C o nti n u o us  E C G r e c or di n g  vi a  a  H olt er  m o nit or 
•   Bl o o d  s a m pl e s  f or  P K  a n al ysis  a p pr o xi m at el y   3 0    mi n ut es  aft er  d osi n g  a n d  1,  2,  3,  4,  6,  8,  a n d 
1 2  h o urs  aft er  d osi n g 
•   Uri n e s a m pl es f or  P K  a n al ysis  will  b e  c oll e ct e d  e v er y ti m e  y o u  uri n at e  
•   S e d ati o n  V A S  will  b e  d o n e  a p pr o xi m at el y  1 t o  2  h o urs  aft er  d osi n g 
Y o u  will  c o nti n u e t o f ast ( n o f o o d  or  dri n k)  f or a p pr o xi m at el y  4  h o urs  aft er  d osi n g.  Y o u  will  b e  a bl e t o 
dri n k  w at er  as  d esir e d  e x c e pt f or  at l e ast  1  h o ur  b ef or e  dr u g  a d mi nistr ati o n  a n d f or  at l e ast  1  h o ur  aft er 
dr u g  a d mi nistr ati o n.  
Y o u  will  b e s er v e d  a st a n d ar d  m e al  a n d  dri n k  at  a p pr o pri at e ti m es t h er e aft er.  
D a y  2 
T h e f oll o wi n g  pr o c e d ur es  will t a k e  pl a c e:  
•   Bri ef  p h ysi c al  e x a m  
•   Bl o o d  a n d  uri n e s a m pl es f or l a b or at or y t ests 
•   Vit al  si g ns  ( bl o o d  pr ess ur e,  h e art  r at e,  br e at hi n g  r at e,  a n d  or al  b o d y  t e m p er at ur e)    will  b e  t a k e n 
a p pr o xi m at el y  2 4  h o urs  aft er  d osi n g 
•   Si n gl e  E C G  will  b e  d o n e  a p pr o xi m at el y  2 4  h o urs  aft er  d osi n g 
•   C o nti n u o us  E C G r e c or di n g  vi a  a  H olt er  m o nit or  will  e n d  a p pr o xi m at el y  2 4  h o urs  aft er  d osi n g 
•   Bl o o d s a m pl es f or  P K  a n al ysis  a p pr o xi m at el y  2 4  h o urs  aft er  d osi n g 
•   Uri n e s a m pl es f or  P K  a n al ysis  will  b e  c oll e ct e d  e v er y ti m e  y o u  uri n at e  
•   Y o u  will  b e  as k e d  h o w  y o u  ar e f e eli n g  a n d if  y o u  h a v e t a k e n  a n y  m e di c ati o ns 
D a y  3 
T h e f oll o wi n g  pr o c e d ur es  will t a k e  pl a c e:  
•   Bl o o d s a m pl es f or  P K  a n al ysis  a p pr o xi m at el y  4 8  h o urs  aft er  d osi n g 
•   Uri n e s a m pl es f or  P K  a n al ysis  will  b e  c oll e ct e d  e v er y ti m e  y o u  uri n at e  
•   Y o u  will  b e  as k e d  h o w  y o u  ar e f e eli n g  a n d if  y o u  h a v e t a k e n  a n y  m e di c ati o ns 
D a y  4 
T h e f oll o wi n g  pr o c e d ur es  will t a k e  pl a c e:  
•   Bri ef  p h ysi c al  e x a m  
•   Vit al  si g ns  ( bl o o d  pr ess ur e,  h e art  r at e,  br e at hi n g  r at e,  a n d  or al  b o d y  t e m p er at ur e)    will  b e  t a k e n 
a p pr o xi m at el y  7 2  h o urs  aft er  d osi n g 
•   Si n gl e  E C G  will  b e  d o n e  a p pr o xi m at el y  7 2  h o urs  aft er  d osi n g 
•   Bl o o d s a m pl es f or  P K  a n al ysis  a p pr o xi m at el y  7 2  h o urs  aft er  d osi n g 
•   Uri n e s a m pl es f or  P K  a n al ysis  will  b e  c oll e ct e d  e v er y ti m e  y o u  uri n at e  
•   Y o u  will  b e  as k e d  h o w  y o u  ar e f e eli n g  a n d if  y o u  h a v e t a k e n  a n y  m e di c ati o ns 
F oll o wi n g  t h e  pr o c e d ur es  o n  D a y  4 ,  y o u    will  b e  dis c h ar g e d  fr o m  t h e  r es e ar c h  sit e  if  t h e  st u d y  st aff  
d et er mi n es it is  m e di c all y  a c c e pt a bl e  f or  y o u  t o l e a v e.  Y o u  will  b e i nstr u ct e d  o n  w h e n t o  r et ur n t o t h e 
r es e ar c h sit e f or  y o ur F oll o w- U p  Visit.  


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  7  of  1 5  
 
F oll o w- U p  Visit  ( D a y  1 1) 
T h e f oll o wi n g  pr o c e d ur es  will  t a k e  pl a c e: 
•   Y o u  will  b e  as k e d  h o w  y o u  ar e f e eli n g  a n d if  y o u  h a v e t a k e n  a n y  m e di c ati o ns  
•   Vit al  si g ns ( bl o o d  pr ess ur e, h e art r at e ,  br e at hi n g r at e,  a n d  or al  b o d y t e m p er at ur e) 
•   Si n gl e  E C G  
•   Bri ef  p h ysi c al  e x a mi n ati o n  
•   Bl o o d s a m pl es f or l a b or at or y t ests 
•   Uri n e  pr e g n a n c y t est f or f e m al es  
Y o ur  p arti ci p ati o n i n t h e st u d y  will  e n d  at t his ti m e.  
E a rl y  T e r mi n ati o n 
S h o ul d  y o u  st o p  y o ur  p arti ci p ati o n  i n  t h e  st u d y  e arl y ,  t h e  st u d y  st aff  will  r e q u est  t h at  y o u  h a v e  t h e 
f oll o wi n g  pr o c e d ur es  d o n e: 
•   Y o u  will  b e  as k e d  h o w  y o u  ar e f e eli n g  a n d if  y o u  h a v e t a k e n  a n y  m e di c ati o ns 
•   Vit al si g ns ( bl o o d  pr ess ur e,  h e art r at e,  br e at hi n g r at e,  a n d  or al  b o d y t e m p er at ur e) 
•   Si n gl e  E C G  
•   Bri ef  p h ysi c al  e x a mi n ati o n  
•   Bl o o d s a m pl es f or l a b or at or y t ests 
•   Uri n e  pr e g n a n c y t est f or f e m al es  
H o w  l o n g   p r o c e d u r es    m a y  t a k e   a n d  t h e  l e n gt h   of  ti m e  f o r   r es e a r c h   sit e   r est ri cti o ns  is   a n 
a p p r o xi m ati o n  a n d    m a y   b e  l o n g e r   b as e d   o n   ot h e r   p r o c e d u r es   a n d  st u d y   a cti viti es  s c h e d ul e d 
d u ri n g  y o u r st a y. 
A D DI TI O N A L  D R U G  A N D  A L C O H O L  S C R E E N S  
R a n d o m  uri n e  dr u g  a n d  al c o h ol  s cr e e ns t o  e ns ur e  c o m pli a n c e   m a y  b e  r e p e at e d  at  a n y ti m e  d uri n g t h e 
st u d y if t h e  st u d y  st aff s us p e cts  al c o h ol  or  dr u g  us e.  If  y o u t est  p ositi v e f or  dr u g  or  al c o h ol  us e,  at  a n y 
ti m e  aft er t h e first  d os e  of st u d y  dr u g,  y o u  will  b e  dis c o nti n u e d fr o m t h e st u d y. 
C O N T R O L L E D  S E A R C H  
D esi g n at e d  st u d y  st aff r es er v es t h e ri g ht t o  d o  a  c o ntr oll e d  s e ar c h  b y  h a vi n g  y o u  p ut  o n  a  g o w n i n  or d er 
t o  h a v e  y o ur  cl ot h es  a n d  p ers o n  c h e c k e d  f or  dis all o w e d ( pr o hi bit e d)  it e ms t h at  m a y  h a v e  b e e n  br o u g ht 
i nt o t h e r es e ar c h sit e.  T his  s e ar c h i n v ol v es r e m o vi n g  all  u n d er g ar m e nts  as  w ell  as  p utti n g  o n  a  g o w n  s o 
t h at t h er e is  n o  pl a c e t h e  dis all o w e d it e ms  c o ul d  b e  k e pt. 
R E S T RI C TI O N S  
T hr o u g h o ut  y o ur  e ntir e  p arti ci p ati o n i n t h e r es e ar c h st u d y,  t h e f oll o wi n g r estri cti o ns  will  a p pl y: 
•   D o  n ot  p arti ci p at e i n  a n y  h e a v y  e x er cis e  or  str e n u o us  a cti viti es  2 4  h o urs  ( 1 d a y)  pri or t o  d osi n g  wit h 
st u d y  dr u g  a n d  u ntil  aft er t h e  f oll o w- u p  visit  
•   R efr ai n  fr o m  dri n k i n g  al c o h ol  d uri n g  t h e  st u d y   fr o m  2 4  h o urs  b ef or e  a d missi o n  u ntil  aft er   t h e 
f oll o w- u p  visit 
•   D o   n ot   c o ns u m e   a n y   p o p p y   s e e ds,  gr a p efr uit,   S e vill e   or a n g es,   gr a p efr uit - c o nt ai ni n g  f o o ds   or 
b e v er a g es ,  a n d  S e vill e or a n g es - c o nt ai ni n g f o o ds  or  b e v er a g es  f or  at l e ast  7 d a ys  b ef or e  d osi n g  wit h 
st u d y  dr u g  a n d  u ntil  aft er t h e f oll o w- u p  visit 
•   D o  n ot  c o ns u m e  a n y  c aff ei n e/ x a nt hi n e -c o nt ai ni n g f o o ds  or  b e v er a g es (f or  e x a m pl e  c off e e, t e a,  c ol a, 
c h o c ol at e ,  c aff ei n e-c o nt ai ni n g  s o d a  ( M o u nt ai n  D e w,  Dr.  P e p p er,  et c.),  c aff ei n e/ x a nt hi n e - c o nt ai ni n g 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  8  of  1 5  
 
“ e n er g y  dri n ks ” ( R e d  B ull,  E xtr e m e  E n er g y  S h ot,  et c.)  1 6  h o urs  pri or t o  c h e c k -i n a n d  u ntil  aft er  t h e 
f oll o w- u p  visit 
•   D o  n ot  s m o k e  or  us e  a n y  ni c oti n e  pr o d u cts  f or  at l e ast  9 0  d a ys  b ef or e  d o si n g  wit h  st u d y  dr u g  a n d 
u ntil  aft er  t h e f oll o w-u p  visit  
•   D o  n ot  us e  of  a n y  p r es cri pti o n,  n o n- pr es cri pti o n, t o pi c al  m e di c ati o ns,  or  h er b al r e m e di es f or at l e ast 
1 4  d a ys  b ef or e  d osi n g  wit h  st u d y  dr u g  (t his r estri cti o n  p eri o d  m a y  b e l o n g er [ 3 0 d a ys]  d e p e n di n g  o n 
t h e  dr u g) * 
•   Y o u  m ust  n ot  h a v e  us e d  a n y i n v esti g ati o n al  dr u g  wit hi n  3 0  d a ys  pri or t o  d osi n g  wit h st u d y  dr u g. 
Y o u    m ust  n ot  h a v e  d o n at e d  bl o o d  of  a p pr o xi m at el y  5 0 0    m L  of    m or e    wit hi n  5 6  d a ys  or  pl as m a 
d o n ati o n  wit hi n  7  d a ys  of s cr e e ni n g. 
*  T h e  us e  of  s o m e  m e di c ati o ns  m a y  b e  all o w e d  b y t h e  st u d y  st aff  (f or  e x a m pl e,  h or m o n e  r e pl a c e m e nt 
t h er a p y,  h or m o n al  c o ntr a c e pti o n,  a c et a mi n o p h e n) 
B L O O D  S A M P L E S  
Bl o o d  s a m pl es  will  b e  dr a w n  b y  si n gl e  n e e dl e -sti c ks or i ntr a v e n o us (I V)  c at h et er,  as  d et er mi n e d  b y t h e 
st u d y  st aff. A n I V  c at h et er is  a  s m all  pl asti c t u b e i ns ert e d i nt o  y o ur  ar m  v ei n  b y  a  n e e dl e.  T h e  n e e dl e is 
r e m o v e d,  b ut t h e t u b e t e m p or aril y r e m ai ns i n  y o ur  v ei n.  T his t u b e  all o ws t h e r e m o v al  of  bl o o d  wit h o ut 
h a vi n g  t o  sti c k   y o u   e a c h  ti m e.    T h e  t ot al   a m o u nt   of   bl o o d   dr a w n    will   b e  a p pr o xi m at el y    1 4 7 m L 
( a p pr o xi m at el y ¾  c u p ).  F or  c o m p aris o n,  a  st a n d ar d  bl o o d  d o n ati o n  at  a  bl o o d  c oll e cti o n  c e nt er,  o n c e i n 
a n y  5 6 - d a y  p eri o d, is  a b o ut  2  c u ps ( 5 0 0  m L) of  bl o o d. 
A d diti o n al  bl o o d  s a m pl es  m a y  b e  dr a w n  d uri n g t h e  st u d y , if t h e st u d y  st aff c o nsi d ers  it  n e c ess ar y  f or 
m o nit ori n g  y o ur  h e alt h. 
S U B J E C T  R E S P O N SI BI LI TI E S  
As   a  s u bj e ct  i n  t his   st u d y,   y o u   h a v e   c ert ai n   r es p o nsi biliti es  t o   h el p   e ns ur e   y o ur   s af et y.    T h es e 
r es p o nsi biliti es  ar e list e d  b el o w. 
•   C o m pl et e  all r e q uir e d  visits  
•   F oll o w  a ll i nstr u cti o ns fr o m st u d y st aff 
•   R e p ort  all  p ossi bl e  si d e  eff e cts  a n d  m e di c al  pr o bl e ms t o t h e  st u d y st aff 
•   I nf or m t h e st u d y st aff if  y o u  d e ci d e t o  dis c o nti n u e  y o ur  p arti ci p ati o n i n t h e st u d y  
•   Y o u  m a y  b e  as k e d  t o  c o m pl et e  t h e  e arl y  t er mi n ati o n  visit  pr o c e d ures  as  d es cri b e d  i n t his  c o ns e nt 
f or m 
P O T E N TI A L  RI S K S  A N D  DI S C O M F O R T S  
Si n c e I N D V -2 0 0 0  h as  n ot  b e e n  st u di e d i n  p e o pl e, t h e  si d e  eff e cts  ar e  u n k n o w n.  E v er y o n e t a ki n g  p art i n 
t h e st u d y  will  b e  w at c h e d  c ar ef ull y. 
R es e ar c h  s t u di es  c o n d u ct e d i n  d o gs a n d  r ats  wit h t his  st u d y  dr u g  w er e  d o n e  at  d os es  hi g h er t h a n  w h at 
y o u  c o ul d  b e r e c ei vi n g.  T h os e st u di es s h o w e d  a n i n cr e as e i n  bl o o d  pr ess ur e  i n  d o gs ( d os e  of  1 0 0  m g/ k g) 
a n d  a  d e cr e as e i n l o c o m ot or  a cti vit y ( m us c ul ar  a n d  s k el et al  s yst e ms) i n r at  st u di es ( d os e  of  5 0 0  m g/ k g) . 
T h er e    m a y  b e  c h a n g es  i n  y o ur  h e art  r h yt h m.        H o w e v er,  n o  si g nifi c a nt  eff e cts    w er e  o bs er v e d  i n  t h e 
c e ntr al  n er v o us s yst e m  or r es pir at or y s yst e m.    
It is  als o  p ossi bl e t o  e x p eri e n c e  a  s eri o us  all er gi c r e a cti o n,  w hi c h  c o ul d  b e c o m e lif e-t hr e at e ni n g  or f at al. 
S y m pt o ms  of  a n  all er gi c r e a cti o n i n cl u d e r as h,  hi v es, it c hi n g, s w elli n g  of t h e  m o ut h, f a c e, li ps  or t o n g u e, 
di z zi n ess, ti g ht n ess i n t h e  c h est  or  tr o u bl e  br e at hi n g. 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  9  of  1 5  
 
If  y o u  d o  n ot  u n d erst a n d  w h at  a n y  of t h es e  si d e  eff e cts  m e a n,  pl e as e  as k  t h e st u d y  st aff t o  e x pl ai n t h em 
t o  y o u. 
E C G  ris ks  
E C G  p at c h es  m a y  c a us e  a  s ki n  r e a cti o n  s u c h  as  r e d n ess  or it c hi n g.  Y o u  m a y  als o  e x p eri e n c e l o c ali z e d 
s ki n  dis c o mf orts  a n d / or  h air l oss  ass o ci at e d  wit h t h e  pl a c e m e nt  of  E C G  p at c h es. 
Bl o o d  S a m pl e  ris ks  
L o c al  p ai n,  br ui si n g,  bl e e di n g, i nfl a m m ati o n  or i nf e cti o n  mi g ht  o c c ur  at t h e sit e  of t h e  n e e dl e sti c k  or I V 
c at h et er  w h er e  bl o o d is  dr a w n.  T h er e is  a  p ossi bilit y  of  di z zi n ess  or  f ai nti n g  w hil e  y o ur  bl o o d is  b ei n g 
dr a w n.  Pr e c a uti o ns  will  b e t a k e n t o  mi ni mi z e t h e  a b o v e  c o m p li c ati o ns. 
U n k n o w n/ U nf o r es e e a bl e  Ris ks  
I n  a d diti o n t o t h e ris ks list e d  a b o v e, t h er e  m a y  b e  s o m e  u n k n o w n  or i nfr e q u e nt  a n d  u nf or es e e a bl e ris ks 
ass o ci at e d    wit h  t h e   us e   of  t his  st u d y   dr u g,  i n cl u di n g  all er gi c  r e a cti o n   or  i nt er a cti o n    wit h  a n ot h er 
m e di c ati o n.  Y o u  m ust  n otif y t h e  st u d y  st aff i m m e di at el y if  y o u  e x p eri e n c e  a n  all er gi c  r e a cti o n  s u c h  as 
r as h,  hi v es,  or it c hi n g.  If  y o u  e x p eri e n c e  a n y  of  t h e  a b o v e  s y m pt o ms,  y o u  m ust  c all t h e  st u d y  st aff  at 
9 1 3- 6 9 6- 1 6 0 1. 
P R E G N A N C Y/ BI R T H  C O N T R O L  
F e m al es   
T h e  eff e ct  of  I N D V- 2 0 0 0 o n t h e  e m br y o, f et us,  or  n ursi n g i nf a nt  is  u n k n o w n  at t his ti m e.  T h er ef or e, it is 
i m p ort a nt  t h at    w o m e n    w h o   ar e   pr e g n a nt,    m a y   b e c o m e   pr e g n a nt   or    w h o   ar e   br e astf e e di n g  N O T 
p arti ci p at e i n t his st u d y.  F e m al es  m ust  b e  of  n o n- c hil d b e ari n g  p ot e nti a l t o  p arti ci p at e i n t his st u d y. 
F e m al e s u bj e cts  m ust :  
•   n ot  h a v e  a  ut er us 
•   h a v e  b e e n  s ur gi c all y  st erili z e d  b y  c o m pl et e  h yst er e ct o m y,  bil at er al  o o p h or e ct o m y , bil at er al t u b al 
li g ati o n (t u b es ti e d)  
•   h a v e  p er m a n e nt l a c k  of  o v ari a n f u n cti o n  d u e t o  o v ari a n f ail ur e  or s ur gi c al r e m o v al  of t h e  o v ari es 
•   b e  p ost- m e n o p a us al ( at l e ast  1 2  m o nt hs  wit h o ut  a  m e ns es,  a n d  c o nfir m e d  b y  bl o o d t est) 
M al es  
T h e  eff e ct  of  I N D V- 2 0 0 0 o n t h e  e m br y o, f et us,  or  n ursi n g i nf a nt  is  u n k n o w n  at t his ti m e.  T h e  eff e ct  of 
t h e  st u d y  dr u g  o n t h e  m al e r e pr o d u cti v e  s yst e m is  u n k n o w n.  T h er ef or e, if  y o u  ar e  s e x u all y  a cti v e  wit h  a 
f e m al e  p art n er  of  c hil d-b e ari n g  p ot e nti al  y o u  M U S T  us e  a  c o n d o m  pl us  a n  a p pr o v e d  m et h o d  of  eff e cti v e 
c o ntr a c e pti o n  fr o m  t h e  ti m e  of  s cr e e ni n g  a n d  u ntil  9 0  d a ys  aft er  t h e  l ast  d os e  of  t h e  st u d y  dr u g. 
A p pr o v e d  m et h o ds  of  eff e cti v e  c o ntr a c e pti o n i n cl u d e:  
•   C o m bi n e d ( o 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 
i n cl u di n g  or al, 
i ntr a v a gi n al,  or 
tr a ns d er m al  m et h o ds 
•   I m pl a nt a bl e i ntr a ut eri n e 
d e vi c e (I U D)  
•   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 
i n cl u di n g  or al, i nj e ct a bl e, 
i m pl a nt a bl e,  a n d 
i ntr a ut eri n e  h or m o n e-
r el e asi n g s yst e m (I U S) 
•   S ur gi c al st erili z at i o n (f or 
e x a m pl e,  v as e ct o m y  or 
bil at er al t u b al li g ati o n)  
•   M al e  c o n d o m  wit h 
s p er mi ci d al  g el/f o a m  or 
wit h f e m al e  c a p  or 
di a p hr a g m ( d o u bl e 
b arri er)  
Y o u  m a y  N O T  d o n at e  s p er m  at  a n y ti m e t hr o u g h t h e  e ntir e  st u d y  a n d f or  at l e ast  9 0  d a ys  aft er  y o ur  l ast 
d os e  of t h e st u d y  dr u g. 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  1 0  of  1 5  
 
If  y o ur  f e m al e  p art n er  h as  b e c o m e  pr e g n a nt  d uri n g t h e  c o urs e  of t h e  st u d y,  y o ur  p art n er  will  b e  as k e d 
f or  p er missi o n t o  c oll e ct i nf or m ati o n  a b o ut t h e  pr e g n a n c y  a n d its  o ut c o m e  b y  si g ni n g  a  s e p ar at e  c o ns e nt 
f or m. 
N E W I N F O R M A TI O N  
Y o u  will  b e i nf or m e d  v er b all y  a n d i n  writi n g  of  a n y  n e w i nf or m ati o n, fi n di n gs  or  c h a n g es t o t h e  w a y t h e 
r es e ar c h  will  b e  p erf or m e d t h at  mi g ht i nfl u e n c e  y o ur  willi n g n ess t o  c o nti n u e  y o ur  p arti ci p ati o n i n t his 
st u d y.  
P O T E N TI A L  B E N E FI T S  A N D  A L T E R N A TI V E  T R E A T M E N T S  
Si n c e t h e  dr u g i n t his  st u d y  is n ot  b ei n g  gi v e n t o tr e at  a n y  s y m pt o ms  or ill n ess, t h er e  will  b e  n o  m e di c al 
b e n efit.  A n  alt er n ati v e  w o ul d  b e t o  n ot t a k e  p art i n t h e st u d y. 
C O S T S  A N D  C O M P E N S A TI O N  
T h er e is  n o  c h ar g e  t o  y o u f or  p arti ci p ati n g i n t his  r es e ar c h  st u d y.  Th e  st u d y  s p o ns or  p a ys  all t h e  st u d y 
c ost s  ass o ci at e d  wit h  c o n d u cti n g t his  st u d y . Alt as ci e n c es  Cli ni c al  K a ns as, I n c.  a n d  Alt as ci e n c es  Cli ni c al 
K a ns as ,  P. A.  will r e c ei v e  p a y m e nt fr o m t h e s p o ns or f or  c o n d u cti n g t his r es e ar c h st u d y. 
F or  y o ur  p arti ci p ati o n i n t his st u d y,  y o u  m a y  b e  c o m p e ns at e d  as f oll o ws: 
Visit  1  
S cr e e ni n g  
 
Visit  2  - 5  
D a y  -1 t o  -3 I n p ati e nt  
 
Visit  6  
D a y  4  Dis c h ar g e  
 
Visit  7  
D a y  1 1  E n d -of -St u d y  Offi c e  Visit  
 
C o m pl eti o n  A m o u nt  
 
T ot al  u p t o  
 
 
Visit  1  will  b e  c o m p e ns at e d i n t h e  a m o u nt  of   
  at t h e  c o m pl eti o n  of t h e  visit. 
Visits  2 t hr o u g h  5  will  b e  c o m p e ns at e d i n t h e  a m o u nt  of   
  u p o n  dis c h ar g e  at  Visit  6. 
Visit  7  will  b e  c o m p e ns at e d i n t h e  a m o u nt  of   
  at t h e  c o m pl eti o n  of t h e  visit. 
C o m p e ns ati o n    will  b e  iss u e d  i n  t h e  f or m  of  a  c h e c k,  pr e -l o a d e d    M ast er C ar d,  or  c as h.   T h e  f or m  of 
c o m p e ns ati o n  will  b e  d et er mi n e d  b y t h e st u d y st aff. 
U ns c h e d ul e d  visits  m a y  b e  c o m p e ns at e d  u p t o   
  as  d et er mi n e d  b y t h e st u d y st aff. 
All  visits    m ust  b e  c o m pl et e d    wit hi n  t h e  s c h e d ul e d  ti m efr a m e  i n  or d er  t o  r e c ei v e  t h e  e n d  of  st u d y 
c o m pl eti o n  a m o u nt  of   
  o n  Visit  7.  F ail ur e t o  c o m pl et e  all  visits  wit hi n t h e  all o w a bl e ti m efr a m e  will 
m a k e  y o u i n eli gi bl e t o r e c ei v e t h e  c o m pl eti o n  a m o u nt. 
M o n e y  m a y  b e  d e d u ct e d fr o m  y o ur  st u d y  c o m p e ns ati o n if  y o u  d o  n ot f oll o w t h e i n -h o us e r ul es  or  ot h er 
r e as o n a bl e i nstr u cti o ns  gi v e n  b y t h e  st u d y  st aff. F or  e x a m pl e, if ill e g al  s u bst a n c es  ar e  br o u g ht i nt o t h e 
r es e ar c h  sit e  or  y o u  ar e  f o u n d  t o  b e  usi n g  a n  ill e g al  s u bst a n c e    w hil e  i n  h o us e,  u p  t o  h alf  of  y o ur 
pr e vi o usl y  e ar n e d  a m o u nt  m a y  b e  d e d u ct e d  a n d  y o u  m a y  b e  wit h dr a w n fr o m t h e  st u d y  as  d et er mi n e d  b y 
t h e st u d y st aff. 
If  y o u  wit h dr a w  or  ar e  wit h dr a w n fr o m t h e  st u d y  e arl y,  y o u  will  o nl y  b e  c o m p e ns at e d f or t h e  visits t h at 
y o u  c o m pl et e.  


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  1 1  of  1 5  
 
If   y o u  dis c o nti n u e  fr o m  t h e  i n-h o us e  p orti o n  of  t h e  st u d y  e arl y  f or  a n y  r e as o n,  y o u    will   o nl y  b e 
c o m p e ns at e d   o n e   ni g ht’s   e ar n e d  sti p e n d.   T h e  r e m ai n d er   of   y o ur   e ar n e d  i n -h o us e  sti p e n d    will   b e 
c o m p e ns at e d t o  y o u  o n t h e  ori gi n all y s c h e d ul e d st u d y  d a y/ d at e  of  dis c h ar g e fr o m t h e  i n-h o us e  p orti o n  of 
t h e st u d y. 
Y o u  m a y  b e r e q uir e d t o r e p ort t h e  c o m p e ns ati o n r e c ei v e d f or t his  st u d y t o t h e I nt er n al  R e v e n u e  S er vi c e 
as t a x a bl e i n c o m e.  A c c or di n g t o t h e I R S  (I nt er n al  R e v e n u e  S er vi c e)  g ui d eli n es,  y o u  will  b e r es p o nsi bl e 
f or  p a yi n g  t a x es  o n  a n y  c o m p e ns ati o n  t h at  y o u  r e c ei v e  fr o m  y o ur  st u d y  p arti ci p ati o n.  Alt as ci e n c es  
Cli ni c al  K a ns as, I n c.  will  s e n d  y o u  a  1 0 9 9 -f or m f or t his  p ur p os e. Alt as ci e n c es  Cli ni c al  K a ns as , I n c. will 
als o  r e p ort t o t h e  I R S  a n y  c o m p e ns ati o n t h at  y o u  r e c ei v e t h at t ot als  $ 6 0 0. 0 0  or  m or e  f or t h e  c al e n d ar 
y e ar.   Y o u  m ust t ell  Alt as ci e n c es  Cli ni c al   K a ns as,  I n c.  of  y o ur  n e w  m aili n g  a d dr ess if  y o u  m o v e  aft er 
y o ur  p arti ci p ati o n i n  a st u d y.  T his is t o   m a k e s ur e  y o u r e c ei v e  y o ur  1 0 9 9 f or  y o ur  y e ar- e n d t a x r e p orti n g. 
R E S E A R C H -R E L A T E D I N J U RI E S  
If  y o u  h a v e  a n y  si d e  eff e cts t o t h e  st u d y  dr u g  or  c h a n g es i n  y o ur  p h ysi c al  or  m e nt al  c o n diti o n  d uri n g t h e 
c o urs e  of t h e st u d y,  y o u  m ust i m m e di at el y  n otif y  t h e st u d y st aff  at 9 1 3- 6 9 6- 1 6 0 1. 
If  y o u  ar e i nj ur e d  or  g et  si c k  b e c a us e  of  b ei n g i n t his  r es e ar c h,  c all t h e  st u d y  d o ct or i m m e di at el y.  T h e 
st u d y  d o ct or  will  pr o vi d e  e m er g e n c y  m e di c al tr e at m e nt.  Y o ur i ns ur a n c e  m a y  b e  bill e d f or t his tr e at m e nt. 
T h e  s p o ns or  will  p a y  a n y  c h ar g es t h at  ar e  n ot  c o v er e d  b y i ns ur a n c e  p oli c y  or t h e  g o v er n m e nt,  pr o vi d e d 
t h e i nj ur y  w as  n ot  d u e t o a n  u n d erl yi n g ill n ess  or  c o n diti o n  a n d  w as  n ot  c a us e d  b y  y o u  or  s o m e  ot h er 
t hir d  p art y.  N o  ot h er  p a y m e nt is r o uti n el y  a v ail a bl e fr o m t h e st u d y  d o ct or  or s p o ns or. 
F urt h er i nf or m ati o n  r e g ar di n g  m e di c al tr e at m e nt  f or  r es e ar c h -r el at e d i nj uri es  c a n  b e  o bt ai n e d  fr o m t h e 
st u d y st aff.  Y o u  m ust  n otif y t h e st u d y st aff i m m e di at el y  of  a n y p ossi bl e  r es e ar c h-r el at e d i nj ur y. 
R E L E A S E  O F  Y O U R  M E DI C A L  R E C O R D S  A N D  P RI V A C Y  
Y o ur  r e c or ds  of  b ei n g  i n  t his  st u d y   will  b e  k e pt  pri v at e  e x c e pt   w h e n  or d er e d  b y  l a w.   T h e  f oll o wi n g 
p e o pl e  will  h a v e  a c c ess t o  y o ur st u d y r e c or ds: 
•   St u d y  st aff 
•   St u d y  s p o ns or  a n d t h eir r e pr es e nt ati v es ( m o nit ors,  a u dit ors, C o ntr a ct  R es e ar c h  Or g a ni z ati o n ( C R O) ) 
•   T h e   F o o d  a n d  Dr u g  A d mi nistr ati o n ( F D A) 
•   Ot h er  g o v er n m e nt al  a g e n ci es  
•   Mi d l a n ds I n d e p e n d e nt R e vi e w  B o ar d  ( M LI R B) 
T h e  I n d e p e n d e nt  R e vi e w  B o ar d (I R B) is  a  gr o u p  of i n di vi d u als r es p o nsi bl e f or t h e r e vi e w  a n d  a p pr o v al 
of r es e ar c h  pr o p os e d t o  b e  c o n d u ct e d. 
T h e  I R B a n d  g o v er n m e nt al  a g e n ci es  m a y i ns p e ct  a n d  c o p y  y o ur r e c or ds,  w hi c h  m a y  h a v e  y o ur  n a m e  o n 
t h e m.  T h er ef or e,  y o ur t ot al  pri v a c y  c a n n ot  b e  g u ar a nt e e d.  If t h e  st u d y  r es ults  ar e  pr es e nt e d  at  m e eti n gs 
or  pri nt e d i n  p u bli c ati o ns,  y o ur  n a m e  will  n ot  b e  us e d. 
Y o ur  bl o o d  a n d  uri n e  s a m pl es  c oll e ct e d  d uri n g t h e  st u d y  m a y  b e  us e d t o  p erf or m  a d diti o n al t ests  r el at e d 
t o  I N D V-2 0 0 0  or its  m e c h a nis m  of  a cti o n  aft er t h e  st u d y is  c o m pl et e d  wit h o ut  a d diti o n al  c o ns e nt  fr o m 
y o u.  


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  1 2  of  1 5  
 
RI G H T  T O  WI T H D R A W  O R  R E M O V A L  F R O M  S T U D Y  
Y o u  ar e fr e e t o  wit h dr a w fr o m t his  st u d y  at  a n y ti m e.  Y o u  s h o ul d i nf or m t h e  st u d y  st aff i m m e di at el y if 
y o u  i nt e n d  t o   wit h dr a w.   Y o ur  d e cisi o n  t o  p arti ci p at e  i n  t his  st u d y   will  i n v ol v e  n o  p e n alt y  or  l oss  of 
b e n efits t o  w hi c h  y o u  ar e  ot h er wis e  e ntitl e d. 
T h e  st u d y  st aff i n  c h ar g e  of t h e  st u d y  c a n  r e m o v e  y o u  fr o m t his  st u d y, wit h o ut  y o ur  c o ns e nt , f or  a n y 
r e as o n, i n cl u di n g,  b ut  n ot li mit e d t o: 
•   His/ h er j u d g m e nt t h at  a n y  c o n diti o n  or  cir c u mst a n c e  m a y j e o p ar di z e  y o ur  w elf ar e  or t h e i nt e grit y  of 
t h e st u d y 
•   F ail ur e  o n  y o ur  p art  t o f oll o w t h e i nstr u cti o ns  of t h e st u d y st aff  
•   Dis c o nti n u ati o n  of  t h e  st u d y  b y  t h e  s p o ns or  a n d/ or  st u d y  st aff  p arti ci p ati n g  i n  t h e  st u d y  pri or  t o 
c o m pl eti o n. 
If  y o u  wit h dr a w  or  ar e  wit h dr a w n fr o m t h e  st u d y  aft er  h a vi n g t a k e n t h e  st u d y  dr u g,  y o u  will  b e  as k e d t o 
c o m e  b a c k  t o  t h e  r es e ar c h  sit e  f or  an  e arl y  t er mi n ati o n   visit.    At  t his  visit ,  y o u    will  h a v e  dis c h ar g e 
pr o c e d ur es  p erf or m e d  a n d  bl o o d t ests t o  e ns ur e t h at t h er e  ar e  n o  c h a n g es t o  y o ur  c urr e nt  h e alt h  st at us. 
Y o u  will  b e  as k e d  a b o ut  a n y  c h a n g es i n  y o ur  h e alt h  a n d  a b o ut  a n y  m e di c ati o ns  y o u  ar e t a ki n g. 
C O N FI D E N TI A LI T Y  A N D    A U T H O RI Z A TI O N   F O R    R E L E A S E    O F   P R O T E C T E D    H E A L T H 
I N F O R M A TI O N 
A f e d er al r e g ul ati o n  k n o w n  as t h e  Pri v a c y  R ul e  gi v es  y o u  c ert ai n ri g hts  c o n c er ni n g t h e  pri v a c y  of  y o ur 
h e alt h i nf or m ati o n.  T h e  Pri v a c y  R ul e  w as iss u e d  u n d er  a l a w  c all e d t h e  H e alt h I ns ur a n c e  P ort a bilit y  a n d 
A c c o u nt a bilit y   A ct  of  1 9 9 6  ( HI P A A).  R es e ar c h ers  c o v er e d  b y  t his  r e g ul ati o n  ar e  r e q uir e d t o  g et  y o ur 
a ut h ori z ati o n  ( p er missi o n)  t o  us e  a n d  dis cl os e  (s h ar e    wit h  ot h ers)  a n y  h e alt h  i nf or m ati o n  t h at  c o ul d 
i d e ntif y  y o u.  
If  y o u  si g n  t his  c o ns e nt  f or m,  y o u  ar e  gi vi n g  p er missi o n  f or  t h e  us e  a n d  dis cl os ur e  of  y o ur  h e alt h 
i nf or m ati o n  f or  p ur p os es  of t his  r es e ar c h  st u d y.   Y o u  d o  n ot  h a v e t o  gi v e t his  p er missi o n.  H o w e v er, if 
y o u  d o  n ot,  y o u  will  n ot  b e  a bl e t o  p arti ci p at e i n t h e st u d y.  
W h o  Will  Us e  a n d  Dis cl os e  y o u r  H e alt h I nf o r m ati o n ? 
T h e   s p o ns or  a n d t h e st u d y  st aff  at  Alt as ci e n c es  Cli ni c al  K a ns as,  I n c.  a n d  Alt as ci e n c es  Cli ni c al  K a ns as, 
P. A.  m a y  us e  y o ur  h e alt h  i nf or m ati o n  t o  c o n d u ct,  r e vi e w,  a n d  d et er mi n e  t h e  r es ults  of  t h e  st u d y.   T h e 
st u d y  st aff m a y  als o  us e  y o ur i nf or m ati o n t o  pr e p ar e  r e p orts  or  p u bli c ati o ns  a b o ut t h e  st u d y.  H o w e v er, 
y o ur  n a m e  will  n ot  a p p e ar i n  a n y r e p ort  or  p u bli c ati o n.  T h e  st u d y  st aff m a y  dis cl os e  y o ur i nf or m ati o n t o 
ot h ers,  as  dis c uss e d  i n t h e  n e xt s e cti o n. 
W h at  H e alt h I nf o r m ati o n  Will  B e  Us e d  a n d  Dis cl os e d ? 
T h e  st u d y  st aff  will  r e c or d  y o ur    m e di c al  a n d    m e di c ati o n  hist or y,  a n d  t h e  r es ults  of  e x a mi n ati o ns  a n d 
t ests  d o n e  d uri n g t h e  st u d y  o n  st u d y f or ms.  Y o ur  n a m e  will  n ot  a p p e ar  o n t h e  st u d y f or ms. Y o u  will  b e 
assi g n e d  a  s u bj e ct  i d e ntifi c ati o n  n u m b er.  St u d y  f or ms   m a y  i n cl u d e  y o ur  s u bj e ct  i d e ntifi c ati o n  n u m b er 
a n d  y o ur i niti als.  T h e  st u d y  st aff  will  s e n d t h e  c o m pl et e d  st u d y  f or ms t o t h e  st u d y  s p o ns or.  T his t y p e  of 
i nf or m ati o n  m a y  als o  b e s h ar e d  wit h  ot h ers,  as  d es cri b e d i n t h e  n e xt s e cti o n. 
Y o ur  m e di c al r e c or ds  m a y i n cl u d e  ot h er  h e alt h i nf or m ati o n  a b o ut  y o u  a n d  m a y i n cl u d e  d o c u m e nts t h at 
dir e ctl y i d e ntif y  y o u.  R e pr es e nt ati v es  fr o m t h e  gr o u ps i d e ntifi e d i n t h e  n e xt  s e cti o n  m a y  n e e d t o l o o k  at 
y o ur  m e di c al  r e c or ds t o  m a k e  s ur e t h at t h e i nf or m ati o n  o n t h e  st u d y  f or ms is  c orr e ct  or t h at t h e  st u d y 
w as  c o n d u ct e d  pr o p erl y.   R e vi e ws  li k e  t h at    will  t a k e  pl a c e  at  t h e  r es e ar c h  sit e   or    w h e r e  t h e    m e di c al 
r e c or ds  ar e st or e d  a n d  c a n t a k e  pl a c e  aft er t h e st u d y is  o v er. 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  1 3  of  1 5  
 
I n  a d diti o n,  bi ol o gi c al  s a m pl es  c oll e ct e d  as  p art  of  t his  st u d y   will  c o nt ai n  y o ur  s u bj e ct  i d e ntifi c ati o n 
n u m b er,   b ut    will   n ot   c o nt ai n   y o ur   n a m e.    O nl y    Alt as ci e n c es    will   b e   a bl e  t o   li n k   y o ur   s u bj e ct 
i d e ntifi c ati o n  n u m b er t o  y o ur  n a m e. 
W h o  Will  R e c ei v e  y o u r  H e alt h I nf o r m ati o n ? 
Y o ur st u d y i nf or m ati o n  m a y  b e s h ar e d  wit h t h e f oll o wi n g  p e o pl e  or  gr o u ps: 
•   T h e  st u d y  sp o ns or,  I n di vi or,  or  its  r e pr es e nt ati v es,  i n cl u di n g  c o m p a ni es  it  hir es  t o  pr o vi d e  st u d y -
r el at e d s er vi c es; 
•   Mi dl a n ds  I n d e p e n d e nt  R e vi e w  B o ar d  ( M L I R B) t h at  a p pr o v e d t his  st u d y  a n d  a n y  ot h er  c o m mitt e es 
r es p o nsi bl e f or  o v ers e ei n g t h e r es e ar c h; 
•   G o v er n m e nt  h e alt h  a g e n ci es  (s u c h  as  t h e   F o o d  a n d    Dr u g    A d mi nistr ati o n)  i n  t h e    U . S.  or  ot h er 
c o u ntri es; 
•   H e alt h  c ar e  pr o vi d ers   w h o  pr o vi d e  s er vi c es  t o  y o u  i n  c o n n e cti o n   wit h  t his  st u d y,  a n d  l a b or at ori es 
a n d  ot h er i n di vi d u als  a n d  or g a ni z ati o ns t h at  a n al y z e  y o ur  h e alt h i nf or m ati o n i n  c o n n e cti o n  wit h t his 
st u d y.  
R e pr es e nt ati v es fr o m t h es e  gr o u ps  m a y r e c ei v e i nf or m ati o n fr o m  y o ur  st u d y f or ms  a n d/ or  y o ur  m e di c al 
r e c or ds. 
Will  y o u r I nf o r m ati o n  B e  P r ot e ct e d  b y t h e  P ri v a c y  R ul e  Aft e r It Is  Dis cl os e d t o  Ot h e rs ?  
Alt as ci e n c es   Cli ni c al    K a ns as,  I n c.  a n d    Alt as ci e n c es   Cli ni c al    K a ns as , P. A.  is  r e q uir e d  b y t h e  Pri v a c y 
R ul e  t o  pr ot e ct  y o ur  h e alt h  i nf or m ati o n.    Aft er  y o ur  i nf or m ati o n  is  s h ar e d    wit h  ot h ers,  li k e  t h e  st u d y 
s p o ns or,  it   m a y  n o  l o n g er  b e  pr ot e ct e d  b y  t h e  Pri v a c y   R ul e.   T h e  p e o pl e   w h o  r e c ei v e  t his  i nf or m ati o n 
c o ul d  us e it i n  w a ys  n ot  dis c uss e d i n t his f or m  a n d  c o ul d  dis cl os e it t o  ot h ers.  T h e  s p o ns or  will  us e  a n d 
dis cl os e  y o ur i nf or m ati o n  o nl y f or r es e ar c h  or r e g ul at or y  p ur p os es  or t o  pr e p ar e r es e ar c h  p u bli c ati o ns. I n 
a d diti o n t o  usi n g it  f or t his  st u d y, t h e  s p o ns or  m a y  r e a n al y z e t h e  st u d y  d at a  at  a l at er  d at e  or  c o m bi n e 
y o ur i nf or m ati o n  wit h i nf or m ati o n  fr o m  ot h er  st u di es  f or  r es e ar c h  p ur p os es  n ot  dir e ctl y  r el at e d t o t his 
st u d y.    W h e n  usi n g  t h e  i nf or m ati o n  i n  t h es e   w a ys,  t h e  s p o ns or   m a y  s h ar e  it   wit h  ot h er  r es e ar c h ers,  its 
b usi n ess  p art n ers,  or  c o m p a ni es it  hir es t o  pr o vi d e  r es e ar c h -r el at e d  s er vi c es.  H o w e v er,  y o ur  n a m e  will 
n e v er  a p p e ar i n  a n y s p o ns or f or ms, r e p orts,  d at a b as es,  or  p u bli c ati o ns,  or i n  a n y f ut ur e  dis cl os ur es  b y t h e 
s p o ns or. 
W h at  H a p p e ns if  Y o u   L e a v e t h e  St u d y  E a rl y ? 
If  y o u st o p  p arti ci p ati n g i n t h e st u d y  e arl y, f or  a n y r e as o n, t h e st u d y st aff  will t ell t h e s p o ns or  w h y. If t h e 
st u d y st aff  as ks  y o u t o  c o m e t o  a n y  m or e st u d y  visits  a n d  y o u  a gr e e, t h e st u d y st aff   will s e n d t h e s p o ns or 
i nf or m ati o n fr o m t h os e  visits  as  w ell.  All i nf or m ati o n  c olle ct e d  a b o ut  y o u  m a y  c o nti n u e t o  b e  us e d  a n d 
dis cl os e d. 
W ill  y o u r  A ut h o ri z ati o n  E v e r  E x pi r e ? 
T his  a ut h ori z ati o n  d o es  n ot  h a v e  a n  e x pir ati o n  d at e.   T h e  st u d y  st aff  m a y  n e e d  t o  c orr e ct  or  pr o vi d e 
missi n g i nf or m ati o n  a b o ut  y o u  e v e n  aft er  y o ur  st u d y  p arti ci p ati o n is  o v er.  T h e  r e vi e w  of  y o ur  m e di c al 
r e c or ds  m a y  als o t a k e  pl a c e  aft er t h e st u d y is  o v er. 
M a y  Y o u  T a k e  B a c k  Y o u r   A ut h o ri z ati o n ? 
Y o u  h a v e t h e ri g ht t o r e v o k e  (t a k e  b a c k)  y o ur  a ut h ori z ati o n , at  a n y ti m e , b y  s e n di n g  a  writt e n  n oti c e t o 
t h e St u d y  D o ct or  at  t h e f oll o wi n g  a d dr ess: 
,  M. D.,  P h D,  M P H  
Alt as ci e n c es  Cli ni c al  K a ns as, I n c.  
1 0 1 0 3  M et c alf  A v e n u e 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  1 4  of  1 5  
 
O v erl a n d  P ar k,  K S   6 6 2 1 2 
P h o n e:  ( 9 1 3)  6 9 6- 1 6 0 1 
If  y o u r e v o k e  y o ur  a ut h ori z ati o n, t h e  st u d y  st aff will  n ot  c oll e ct  a n y  n e w  h e alt h i nf or m ati o n  a b o ut  y o u , 
h o w e v er,  t h e y  c a n  c o nti n u e  t o  us e  a n d  dis cl os e  a n y  alr e a d y  c oll e ct e d  i nf or m ati o n  n e c ess ar y  f or  t h e 
r eli a bilit y  of  t h e  st u d y.   T h e  s p o ns or  c a n  als o  still  k e e p  a n d  us e  a n y  i nf or m ati o n  t h at  it  h as  alr e a d y 
r e c ei v e d. If  y o u r e v o k e  y o ur a ut h ori z ati o n,  y o u  c a n  n o l o n g er  c o nti n u e t o  p arti ci p at e i n  t his st u d y.  
M a y  Y o u  L o o k  at  Y o u r  St u d y I nf o r m ati o n ? 
Y o u  h a v e  a  ri g ht t o  s e e  a n d  m a k e  c o pi es  of  y o ur  m e di c al r e c or ds.  H o w e v er, t o  e ns ur e t h e r eli a bilit y  of 
t h e st u d y,  y o u  will  n e e d t o  w ait t o s e e  y o ur st u d y r e c or ds  u ntil t h e st u d y is  c o m pl et e d.  
T his  r es e ar c h  sit e  c o nt ai ns  o p e n  ar e as  a n d  s e mi -pri v at e  sl e e pi n g  r o o ms.  I n  t his  e n vir o n m e nt,  it  is 
p ossi bl e t h at  s o m e o n e  mi g ht r e c o g ni z e  y o u  or  c o ul d  o v er h e ar  y o ur r es p o ns e t o  m e di c al  q u esti o ns  d uri n g 
st u d y  pr o c e d ur es.  W e  ar e  c o n c er n e d  a b o ut  pr ot e cti n g  y o ur  pri v a c y  a n d t a k e  pr e c a uti o ns t o  pr ot e ct it. 
P E R S O N S  T O  C O N T A C T  F O R  Q U E S TI O N S,  C O N C E R N S,  O R  C O M P L AI N T S  
If  y o u  h a v e  a n y  q u esti o ns,  c o n c er ns  or  c o m pl ai nts  a b o ut t his  st u d y,  c all 
,  M. D.,  P h D, 
M P H .  at  9 1 3- 6 9 6- 1 6 0 1. 
If  y o u  h a v e  q u esti o ns  a b o ut  y o ur ri g hts,  g e n er al  q u esti o ns,  c o m pl ai nts  or  c o n c er ns  a b o ut t his r es e ar c h,  or 
q u esti o ns  a b o ut  y o ur ri g hts  as  a  p ers o n t a ki n g  p art i n t his  st u d y,  c all t h e  Mi d l a n ds I n d e p e n d e nt R e vi e w 
B o ar d  ( M LI R B) at ( 9 1 3)  3 8 5 -1 4 1 4  or ( 8 0 0)   6 3 6-4 4 4 5.  If,  at  a n y ti m e  d uri n g  or  aft er  y o ur  p arti ci p ati o n 
i n t his  r es e ar c h,  y o u  w o ul d li k e i nf or m ati o n  or  t o off er i n p ut  a b o ut  y o ur  r es e ar c h  e x p eri e n c e,  y o u  c a n 
c all  M L I R B  or  y o u  c a n  g o t o t h e M L I R B  w e bsit e  at w w w. M LI R B. c o m  a n d  gi v e  y o ur  c o m m e nts.  Eit h er 
w a y  y o u  d o  n ot  h a v e t o  gi v e  y o ur  n a m e, if  y o u  d o  n ot  w a nt t o. 
Y o u  h a v e t h e ri g ht t o  as k  a n y  q u esti o ns  c o n c er ni n g t h e  p ot e nti al  a n d/ or  u n k n o w n  h a z ar ds  of t his  st u d y, 
at  a n y ti m e.  If  y o u  h a v e  a n y  q u esti o ns  c o n c er ni n g  y o ur  p arti ci p ati o n i n t his  st u d y  or if  at  a n y ti m e  y o u 
f e el  y o u  h a v e  e x p eri e n c e d  a  r es e ar c h-r el at e d  i nj ur y  or  a  r e a cti o n  t o  t h e  st u d y  dr u g,  c o nt a ct   
 
,  M. D.,  P h D,  M P H  at  9 1 3- 6 9 6- 1 6 0 1. 
L E G A L  RI G H T S 
Y o u  will  n ot l os e  a n y  of  y o ur l e g al  ri g hts t o  w hi c h  y o u  ar e  ot h er wis e  e ntitl e d  b y  si g ni n g t his  c o ns e nt 
f or m. 


Pr ot o c ol  N o.  I N D V-2 0 0 0 -1 0 1  
S p o ns or  I n di vi or 
P art  1  
V ersi o n  2 
A p pr o v e d  b y  M LI R B  o n  0 6/ 2 3/ 2 0 2 0  
 
 
 
P a g e  1 5  of  1 5  
 
C O N S E N T  
•   Y o u  h a v e r e a d ( or s o m e o n e  h as r e a d t o  y o u) t his I nf or m e d  C o ns e nt  D o c u m e nt. 
•   T his  d o c u m e nt  d es cri b es t h e  p ur p os e  a n d  n at ur e  of t his st u d y. 
•   Y o u  h a v e  h a d ti m e t o r e vi e w t his i nf or m ati o n. 
•   Y o u  h a v e  b e e n  off er e d  a  c h a n c e t o  as k  q u esti o ns.  
•   Y o u  r e c ei v e d s atisf a ct or y a ns w ers t o  y o ur  q u esti o ns. 
•   If  y o u  d o  n ot t a k e  p art i n t h e st u d y,  y o u  will  n ot l os e  a n y  b e n efits. 
•   If  y o u l e a v e t h e st u d y, y o u  will  n ot l os e  a n y  b e n efits.  
•   If  y o u l e a v e t h e st u d y, y o u  will  n ot l os e  a n y l e g al ri g hts.  
•   Y o ur  p arti ci p ati o n i n t his  st u d y is  c o m pl et el y  v ol u nt ar y.  
Y o u  will  r e c ei v e  a  c o p y  of t his si g n e d a n d  d at e d  I nf or m e d  C o ns e nt  D o c u m e nt f or  y o ur r e c or ds. 
Y o u  a gr e e t o  p arti ci p at e i n t his st u d y.  
 
 
 
_ _  _ _/ _ _  _ _  _ _/ _ _  _ _  _ _  _ _                                                                                                    _ _ _  _ _ _: _ _ _  _ _ _             
D   D   M   M   M   Y   Y    Y   Y           S u bj e ct  N a m e  ( Pri nt)   
S u bj e ct  Si g n at ur e   
  
Ti m e  
 
 
 
 
_ _  _ _/ _ _  _ _  _ _/ _ _  _ _  _ _  _ _                                                                                                    _ _ _  _ _ _: _ _ _  _ _ _                     
D    D   M   M   M   Y   Y    Y   Y           P ers o n  C o n d u cti n g      
P ers o n  C o n d u cti n g     
Ti m e  
    C o ns e nt ( Pri nt)   
    
C o ns e nt  Si g n at ur e 
 
 
 

SAP_002.pdf: 
STATISTICAL ANALYSIS PLAN: INDV-2000-101 
 
Protocol Title:  A Phase I, Double-blind, Placebo-controlled, 
Randomized, Single Ascending Dose Study to Assess the 
Safety, Tolerability and Pharmacokinetics of INDV-2000 
(C4X_3256) under Fasting and Fed Conditions in Healthy 
Volunteers 
Final Version: 30 March 2021 
NCT: NCT04413552 
 


 
STATISTICAL ANALYSIS PLAN 
 
 
For: 
Indivior Inc. 
 
 
PROTOCOL No. INDV-2000-101 
 
A Phase I, Double-blind, Placebo-controlled, Randomized, Single Ascending Dose Study to 
Assess the Safety, Tolerability and Pharmacokinetics of INDV-2000 (C4X_3256) under 
Fasting and Fed Conditions in Healthy Volunteers 
 
Version: Final 1.0 
Date: 2021/03/30 
 






 
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
VERSION CONTROL ....................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
TABLE OF TABLES ......................................................................................................................7 
ABBREVIATIONS .........................................................................................................................8 
1 
INTRODUCTION ................................................................................................................10 
2 
STUDY OBJECTIVES ........................................................................................................11 
3 
STUDY DESIGN .................................................................................................................13 
3.1 
General Description .........................................................................................................13 
 
Sample size ............................................................................................................14 
3.1.1
3.2 
Treatments .......................................................................................................................14 
3.3 
Study Procedures .............................................................................................................15 
3.4 
Randomization and Unblinding Procedures ....................................................................15 
3.5 
Subject Completion and Subject Replacement ................................................................16 
3.6 
Dose Escalation and Stopping Criteria ............................................................................16 
 
Dose Escalation Criteria ........................................................................................16 
3.6.1
 
Stopping Criteria ....................................................................................................17 
3.6.2
4 
ANALYSIS POPULATIONS ..............................................................................................18 
4.1 Safety Population ................................................................................................................18 
4.2 PK Population ................................................................................................................18 
5 
STUDY SUBJECTS ............................................................................................................19 
5.1 
Subject Disposition ..........................................................................................................19 
5.2 
Protocol Deviations .........................................................................................................19 
6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...............................20 
6.1 
Demographic and Other Baseline Characteristics ...........................................................20 
6.2 
Substance Use Habits ......................................................................................................20 
6.3 
Medical History ...............................................................................................................20 
6.4 
Prior Medications ............................................................................................................20 
6.5 
Childbearing Potential .....................................................................................................20 
6.6 
Standard High Fat Breakfast ...........................................................................................21 
7 
PHARMACOKINETIC ANALYSIS ..................................................................................22 
7.1 
Missing Values ................................................................................................................22 




 
 
 
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10 
INTERIM ANALYSES AND DATA SAFETY MONITORING .......................................36 
11 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ....................................................37 
12 
GENERAL INFORMATION RELATED TO DATA PRESENTATIONS ........................38 
13 
REFERENCES .....................................................................................................................39 
APPENDIX A 
STUDY SCHEDULE(S) ..............................................................................40 
APPENDIX 1 – Schedule of Events Part I ...............................................................................40 
APPENDIX 2 – Schedule of Events Part II ..............................................................................42 
APPENDIX 3 – Tables for Laboratory Abnormalities .............................................................44 


 
 
 
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TABLE OF TABLES 
Table 1: Objectives and related endpoints .................................................................................... 11 
Table 2: Part I Single Ascending Dose IMP Dosing .................................................................... 15 
Table 3: Pharmacokinetic Parameters ........................................................................................... 23 
 


 
 
 
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ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the plasma drug concentration versus time curve 
BMI 
Body mass index 
CRF 
Case report form 
CS 
Clinically significant 
CSR 
Clinical study report 
CV% 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DTS 
Deviation tracking system 
DMP 
Data Management Plan 
DRSC 
Data Review and Safety Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of study 
FDA 
Food and Drug Administration 
IMP 
Investigational Medicinal Product 
Ln 
Natural log 
ICF 
Informed Consent Form 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCA 
Non compartmental Analysis 
NCS 
Not clinically significant 
NOAEL 
No Observed Adverse Effect Level 
OX1R 
Orexin-1 receptor 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
QTcF 
QT interval corrected with Fridericia’s  formula 
RBC 
Red blood cell 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SE 
Standard error 


 
 
 
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SOC 
System organ class 
SOP 
Standard operating procedure 
 
 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, figures, and listings 
UDS 
Urine Drug Screen 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WBC 
White blood cell 
WHODrug 
World Health Organization Drug  




 
 
 
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2 STUDY OBJECTIVES 
The objectives of the study and corresponding study endpoints are detailed in Table 1. 
Table 1: Objectives and related endpoints 
Objective 
Endpoint(s) 
Analysis 
Primary  
Determine the safety and 
tolerability of INDV-2000 
over a proposed range of 
doses from 1 mg
 
 
     
Incidence, seriousness, severity, and 
relationship to Investigational 
Medicinal Product (IMP) of 
treatment-emergent adverse events 
(TEAEs) in the Safety population  
Refer to Section 9.1.9 
Secondary  
Determine the maximum 
tolerated single dose of 
INDV-2000 
Clinical safety assessments: 
Changes from baseline in laboratory 
evaluations, electrocardiogram 
(ECG) parameters, vital signs, 
physical examination 
Refer to Sections 
9.1.12, 9.1.13, 9.1.14, 
9.1.15 
Characterize 
pharmacokinetics for single 
doses of INDV-2000 
Part I: Single Ascending Dose 
(SAD) under fasted condition:  
Plasma INDV-2000 and M12  
Cmax, tmax, AUC0-last, AUC0-inf, 
AUC(t1-t2; where t1-t2 represents urine collection 
interval t1-t2), t1/2; plasma INDV-2000 
CL/F and Vz/F. 
Additional PK parameters will be 
estimated to support these PK 
endpoints 
 
Refer to Section 7 
Determine potential effects of 
a high-fat meal on drug 
absorption and exposure  
 
Part II: Food interaction: 
Plasma INDV-2000 and M12  
Cmax, tmax, AUC0-last, AUC0-inf, t1/2; 
plasma INDV-2000 CL/F and Vz/F.   
 
Refer to Section 7 
 


 
 
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3 STUDY DESIGN  
3.1 
General Description 
This study will be conducted in 2 parts: 
Part I: Double-blind, placebo-controlled, randomized, single ascending dose (SAD) study with 
INDV-2000 in fasted condition. 
Healthy subjects who meet all eligibility criteria and provide informed consent will be 
randomized in cohorts of 8 subjects, with 6 subjects receiving active drug and 2 subjects 
receiving placebo. The proposed doses will be: 1 mg, 5 mg, 20 mg, 50 mg and 120 mg,
 
  
The goal for Part I is to identify the maximum well-tolerated (MTD) single dose. A sentinel 
group of 2 subjects will be randomized to active or placebo (1 active; 1 placebo) and will be 
dosed ahead of the rest of each cohort. A review of sentinel group safety data for 24 hours after 
dosing will be completed before IMP administration will continue in the remaining 6 subjects (5 
active; 1 placebo) of each cohort. 
Dose escalation decisions between cohorts will be based on a review of available safety data up 
to 72 hours post-dose, particularly TEAEs, vital signs, ECGs, clinical laboratory test results and 
PK data. 
Part II: Open, cross-over, food interaction, single-dose study with INDV-2000, which will be 
given once under fasting conditions and once at completion of a standard FDA high-fat 
breakfast. 
Healthy males (n=8) who meet all eligibility criteria and provide informed consent will receive 
IMP under fed and fasting conditions. Part II will proceed based upon an acceptable safety 
evaluation of Part I. The dose studied will be a well-tolerated dose studied in Part I and not 
exceeding the second highest tolerated dose in Part I. 
A schematic depicting the study design is in Figure 1. 
 
 
 
 
 
 
 
 
 


 
 
 
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Figure 1 Study Schematic- Part I and II 
 
 
a=active, p=placebo, HV=healthy volunteers; SAD=Single ascending dose 
 Sample size 
3.1.1
The sample size is not based on formal power calculations because the study is designed only to 
provide an initial assessment of the safety, tolerability and PK of INDV-2000. The sample size 
used is typical for studies of this nature and should be adequate to assess the parameters 
described. 
3.2 
Treatments 
The following treatment will be administered. 
Part I: IMP will be administered under fasting condition. Subject will fast for at least 10 hrs prior 
to receiving the IMP. Subjects should be advised to avoid food and liquids other than water for at 
least 2 hours prior to dosing until at least 1 hour after dosing. Dose per cohort is detailed in 
Table 2. 
 
 


 
 
 
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Table 2: Part I Single Ascending Dose IMP Dosing 
Cohort 
 
1 
2 
3 
4 
5 
Dose 
 
Active 
N=6  
INDV-2000,  
1 mg  
INDV-2000,    
5 mg 
INDV-2000, 
20 mg 
INDV-2000, 
50 mg 
INDV-2000, 
120 mg 
Placebo 
N=2 
INDV-2000 
Placebo, 1 mg 
INDV-2000 
Placebo, 5 mg 
INDV-2000 
Placebo, 20 mg 
INDV-2000 
Placebo, 50 mg 
INDV-2000 
Placebo, 120mg 
Dosage 
Form 
(Active; 
Placebo) 
 
 
Cohort 
 
6 
7 
8 
9 
Dose 
Active 
N=6  
INDV-2000,  
Dose 6  
INDV-2000,  
Dose 7 
INDV-2000,  
Dose 8 
INDV-2000,  
Dose 9 
Placebo 
N=2 
Placebo, to 
match 
Placebo, to 
match 
Placebo, to 
match 
Placebo, to 
match 
Dosage 
Form 
(Active; 
Placebo) 
 
Part II: IMP will be administered under fasting conditions in Period 1 and at completion of a 
standard FDA high-fat breakfast in Period 2. The same INDV-2000 dose will be used for fed and 
fasted conditions. Dose level is to be determined following Part I. 
3.3 
Study Procedures 
The Schedules of Events for Parts I and II of the study are shown in APPENDIX A.  
3.4 
Randomization and Unblinding Procedures 
Part I of this study will be double-blinded to include the subjects, the Investigator and the 
Sponsor. 
 
 


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The study blind will be broken after the study database has been locked. 
3.5 
Subject Completion and Subject Replacement 
A completed subject is one that has completed the end of study (EOS) visit. Any subject 
withdrawn or discontinuing the study after being dosed will not be replaced. In Part I, subjects 
randomized but not dosed will be replaced, and the replacement subject will be assigned the 
same treatment as the subject being replaced. The study EOS milestone is defined as the last 
subject’s last visit.  
3.6 
Dose Escalation and Stopping Criteria 
 
Dose Escalation Criteria 
3.6.1
Data Review and Safety Committee (DRSC) will review data from cohorts, and will determine if 
the dose can be escalated, or alternatively if any stopping criteria have been met. 
The proposed dose escalation scheme for Part I is described in Table 2, however, a more 
conservative dose escalation may be explored based on PK, safety and/or clinical observations. 
Dose escalation factors will be dependent upon observed safety, tolerability and PK, 
 


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The study will be paused, pending evaluation of all available data by the DRSC, if any of the 
criteria listed below are fulfilled for an individual dosing cohort: 
Adverse Events (AEs): 
Laboratory Abnormalities: 
Vital Signs: 
ECG Criteria: 
 


 
 
 
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4 ANALYSIS POPULATIONS 
4.1 Safety Population 
The Safety population is defined as subjects who received at least one dose of IMP. 
4.2 PK Population 
The PK population is defined as subjects who received at least one dose of INDV-2000 and have 
an adequate number of PK samples collected to derive at least one PK parameter. Subjects 
receiving placebo will not be included in the PK population. 
The Food Effect PK population will be defined as the subset of Part II subjects in the PK 
population that have at least one evaluable PK parameter for at least one meal condition. 
 
 


 
 
 
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5 STUDY SUBJECTS 
5.1 
Subject Disposition 
Subject disposition includes the data of informed consent version, dates of informed consent, 
completion status (i.e., completed or withdrawn), reason for withdrawal, reasons for screen 
failure.  
A signed written ICF (Informed Consent Form) must be obtained from the subject or a legal 
representative before any study assessments or procedures may be performed. Informed consent 
form includes informed consent version visit, informed consent version signed, date of the 
informed consent signed. 
If the subject has permanently discontinued study treatment and is no longer being followed for 
study assessments and procedures (including follow-up procedures), he/she will be considered 
withdrawn from the study. The primary reason for withdrawing from the study must be entered 
into the electronic case report form (eCRF) (e.g., subject is lost to follow-up, Indivior terminates 
the study or Investigator discretion). Other disposition data will include the date of the 
randomization, randomization number and cohort information. 
Subject must meet all check-in criteria both at screening and at check-in (day -1) before entering 
into Part I or Part II of the study. The eCRF includes inclusion/exclusion criteria met/not, criteria 
and comments. A subject will be considered a screen failure if written informed consent was 
obtained but inclusion/exclusion criteria were not met. 
5.2 
Protocol Deviations 
Protocol deviations will be collected 
  PK sampling 
time deviations will be derived programmatically. Protocol deviations will be identified and 
documented
 
 
 
 


 
 
 
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6 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographic and Other Baseline Characteristics 
Demographic data will be collected during the screening of the study. Subject demographics 
include sex, age, ethnicity and race. Other baseline characteristics include height, weight, and 
BMI. 
6.2 
Substance Use Habits 
Data will be recorded at the screening visit. Subjects will not be permitted to drink caffeine-
containing beverages, eat caffeine-containing foods or use caffeine-containing products prior to 
check-in through the EOS visit. In addition to 90 days prior to screening, subjects will refrain 
from smoking and from using e-cigarettes and nicotine-containing products through the EOS 
visit.  
 
Substance use habits data collection includes category of alcohol (substance use collection date, 
intake status, quantity of units, and frequency), nicotine (substance use collection date, intake 
status, quantity of units, frequency, and substance use end date), and xanthine/caffeine 
(substance use collection date and intake status).  
6.3 
Medical History 
A detailed medical history will be obtained during the screening period. Reported terms will be 
coded to System Organ Class (SOC) and Preferred Term (PT) using the Medical Dictionary for 
Regulatory Activities (MedDRA v23.0). Additional information to be collected will include start 
and end dates and whether the condition is ongoing.  
Medical conditions, including surgeries planned before enrolment of the subject in the study, are 
not considered AEs if the conditions were known before study inclusion and should be reported 
in the subject’s medical history.  
Medical history collected during the screening period will include information on the subject's 
complete history of relevant medical conditions, diagnoses, procedures, treatments and any other 
noteworthy medical information. Any updates to medical history information made available 
during the course of the study will be captured. 
6.4 
Prior Medications 
Prior medications are defined as medications taken from signing of informed consent up to time 
of first IMP dose. Data collected will include medication name, timing, dose, route, frequency, 
formulation, indication, related AEs and related medical history. Drug classes and standardized 
names for reported medication names will be coded using WHO-Drug Global September 2020 as 
defined in the study Data Management Plan (DMP). 
6.5 
Childbearing Potential 
Data on childbearing potential will be collected for female subjects only. Data collected will 
include collection date, childbearing potential (yes/no), post-menopausal (yes/no), and other 
reason for non-childbearing potential. 


 
 
 
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6.6 
Standard High Fat Breakfast 
Standard high fat breakfast applies only to Part II, Period 2 of the study. Subjects should 
consume the entire meal in 30 minutes or less, however, the dose must be administered no later 
than 30 minutes after the start of the meal. Data collected will include meal type, date, time, 
percent of meal consumed and comment if meal not provided. 


 
 
 
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7 PHARMACOKINETIC ANALYSIS 
The PK analysis will be performed for the PK population. Data listings, summaries, and figures 
will be done for Parts I and II separately. For Part I, data will be summarized by cohort. For Part 
II, data will be summarized by condition (fasted and fed). 
7.1 
Missing Values 
The lack of a concentration value due to failure to collect the sample, a lost or compromised 
sample, or due to the subject’s early termination from the study will be termed “missing” in the 
dataset, and no imputation will be done. 
If the actual collection time of a postdose PK sample is inadvertently not recorded (considered as 
unknown), but a valid concentration value has been measured, the documentation error will be 
recorded as a protocol deviation, the concentration will be set to missing in the PK analysis and 
will be presented in listings but excluded from summary statistics. 
 
 
 
 
 
 
 
7.3 
Measurements Below the Lower Limit of Quantitation 
Concentration values that are below the lower limit of quantitation (BLQ) prior to the first 
measurable concentration will be set to zero. The BLQ values that are between measurable 
concentrations will be set to missing. If two or more consecutive BLQ concentrations are 
followed by quantifiable concentrations, these quantified values will be set to missing. If a BLQ 
concentration is followed by a quantifiable concentration, and the quantifiable concentration is 
then followed by two or more consecutive BLQ concentrations, the quantifiable concentration 
will be set to missing. The BLQ values following the last quantifiable time points will be set to 
zero. No concentration estimates will be imputed for missing sample values.   
The BLQ rules will be followed for individual and mean PK profile representations and 
summary statistics, but will be reported as ‘<LLOQ’ in the concentration listings. 
7.4 
Actual Time 
The unknown and duplicate actual time will be managed as per 
SOPs. 
The plasma NCA analysis will be based on actual sampling times, except for predose samples, 
which will be reported as zero, regardless of time deviations provided that they are collected 
prior to dosing. 
The individual plasma concentration-time profiles will be presented by dose level using actual 
sampling times whereas the mean plasma concentration-time profiles, and tables of summary 
statistics for concentration-time data will be presented using nominal sampling times.  


 
 
 
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The actual times will be listed in the report. 
7.5 
NCA Analysis 
The following configuration for the NCA analysis (with Phoenix® WinNonlin® version 8, or 
higher) will be used: 
Data:  
 
Serial sampled data 
Model/Dose options Type:  Plasma (200 - 202) 
 Extravascular 
AUC Calculation Method: Linear Up / Log Down (applicable for plasma only) 
Lambda Z (Ȝz) calculation: Best fit method for Ȝz Linear-Log regression  
Reason for exclusion of AUC: In the case where less than 3 consecutive measurable plasma 
concentrations are observed, the AUC parameters will not be estimated. 
The plasma PK parameters requiring Ȝz will not be estimated, and will be presented as not 
calculated (NC), if at least one of the following criteria is not met: 
x R2 >80%  
x The terminal phase consists of less than 3 data points or 
x %AUCextrap < 20%    
The following PK parameters will be calculated for INDV-2000 and M12: 
Table 3: Pharmacokinetic Parameters 
Parameter 
Definition 
Cmax 
Maximum observed plasma concentration  
Cmax/D 
Dose-normalized Cmax (INDV-2000 only) 
tmax 
Time of maximum observed plasma concentration; if the maximum 
observed concentration is not unique, then the first maximum is used 
AUC0-last 
Area under the concentration time curve from the time of last dosing to 
tlast  
AUC0- last/D 
Dose-normalized AUC0-last (INDV-2000 only) 
AUC0-inf 
Area under the concentration time curve extrapolated to infinity, 
calculated as AUC0-last + Clast/ȜZ, where Clast is the measured 
concentration at time tlast 
AUC0-inf/D 
Dose-normalized AUC0-inf (INDV-2000 only) 
AUC(t1-t2) 
Area under the plasma concentration-time curve from t1 to t2 where t1 
and t2 represents urine collection interval t1-t2 shorter than the 


 
 
 
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Parameter 
Definition 
scheduled interval of 0-T. 
Note: This AUC will be estimated to support calculation of CLr over a 
truncated interval in the event a void is missed during a collection 
interval resulting in a shorter interval than the scheduled interval from 
0-T; otherwise, it will not be estimated 
%AUCextrap 
Extrapolated area (i.e. percentage of AUC0-inf due to extrapolation from 
tlast to infinity) 
t1/2 
Plasma terminal elimination half-life, calculated as ln(2)/ȜZ 
CL/F 
Apparent plasma clearance, calculated as Dose/AUC0-inf (INDV-2000 
only) 
Vz/F 
Apparent volume of distribution, calculated as Dose/ ȜZ * AUC0-inf 
(INDV-2000 only) 
The following plasma PK parameters will be used for PK calculation and presented in the 
PK listings only. 
tlast 
Time of last measurable (positive) observed concentration 
R2 
Goodness of fit for the terminal elimination phase 
Number of 
Points 
Number of data points in computing ȜZ 
Ȝz 
Apparent elimination rate constant, estimated by linear regression of the 
terminal linear portion of the log concentration versus time curve 
Ȝz Upper 
Upper limit on time for values included in the calculation of Ȝz 
Ȝz Lower 
Lower limit on time for values included in the calculation of Ȝz 


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7.6 
Pharmacokinetic Statistical Methodology 
 Summary Statistics 
7.6.1
Summary statistics of the individual concentration data and derived parameters will be calculated 
with the built-in Phoenix® WinNonlin® platform and displayed with the same precision as 
received from the bioanalytical laboratory; additional details on precision rules are provided in 
Section7.7. 
Descriptive statistics will be calculated for INDV-2000 and M12 plasma concentrations for each 
nominal time point and for all PK parameters, 
 
Plasma 
 individual concentrations and PK parameters obtained from 
the NCA will be summarized using the following summary statistics: N, minimum (min), 
arithmetic mean (mean), geometric mean (for main plasma PK parameters only), median, 
maximum (max), standard deviation (SD), CV%, and geometric CV% (for main plasma PK 
parameters only). 
  
 
 
 
 
  


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7.7 
Pharmacokinetic Presentation 
In general, all PK summary tables will be presented for the PK population. 
Individual raw PK concentrations will be displayed with 3 significant digits, unless otherwise 
recommended. 
Precision for individual PK parameters will be displayed as follows:  


 
 
 
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x Cmax, AUCs (including dose normalized parameters) and AUC-derived parameters will be 
displayed with the same precision as the raw PK concentration data 
x Parameters associated with time (e.g. tmax and t1/2) will be displayed with 2 decimal places 
x Percentages will be displayed with 2 decimal places 
Terminal phase characterization: 
x Number of points with 0 decimal place 
x R2 and Ȝz with 4 decimal places 
Summary statistics for concentration and PK parameters will be displayed with the same 
precision as the individual values, with the exception of number of observations (N) and 
coefficient of variation (CV%) which will be presented with 0 and 1 decimal place, respectively.  
Concentration profiles will be presented on both linear and semi-log scales. Actual elapsed times 
of PK plasma sample collection relative to dose administration will be included in the listings. 
 


 
 
 
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8 SAFETY ANALYSIS 
8.1 
Adverse Events 
AE monitoring and reporting for each subject will begin after the ICF is signed and will continue 
throughout the study, including the EOS visit, early termination, and follow-up. Data collected 
will include reported term, timing, seriousness, severity, toxicity, relationship to IMP, action 
taken, and outcome. SOCs and PTs for reported terms will be classified using the MedDRA 
version 23.0 terminology as defined in the study DMP.  
8.2 
Concomitant Medications 
Concomitant medications are defined as medications taken at or after the time of first IMP dose. 
Data collected will include medication name, timing, dose, route, frequency, formulation, 
indication, related AEs and related medical history. Drug classes and standardized names for 
reported medication names will be coded using WHO-Drug Global September 2020 as defined 
in the study DMP. 
8.3 
IMP Exposure 
IMP administration will be performed on Day 1 in Part I, Part II Period 1, and Part II Period 2. 
Data collected will include dose, formulation, date/time, route, and whether the subject 
consumed remainder of 240 mL water, taste masking administered, double rinse was conducted, 
capsule consumption was verified, and IMP was administered per protocol. For Part II, whether 
the subject was fasting will also be collected.  
8.4 
Clinical Laboratory Evaluations 
Clinical laboratory data collected will include collection date/time, lab test, result, reference 
range, out-of-range flag, clinical significance, result and comment.   
In the database of laboratory evaluations, results for hematology, chemistry and some urinalysis 
tests (e.g., specific gravity, pH) will be numeric and results for the remaining urinalysis tests, 
urine drug screen, serology, and pregnancy tests will be reported as text. 
The out-of-range flag will be reported as abnormal, high, low, or normal. Abnormal test results 
will be further categorized as clinically significant, not clinically significant, repeated, or to be 
controlled. 
The following clinical laboratory tests will be performed according to the schedule in 
APPENDIX A: 
Hematology 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with differential (absolute 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 


 
 
 
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count) 
 
Urinalysis: 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Leucocyte esterase 
Microscopic examination of sedimenta 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Hormone Panel: 
Follicle Stimulating Hormone 
 
Pregnancy: 
Serum hCG 
 
Screening Only: 
Hemoglobin A1c 
Hepatitis B surface Antigen 
Hepatitis C Antibody 
HIV-1 and -2 antibodies 
Prothombin Time (PT) with INR 
PTT  
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase 
Gamma-glutamyl transferase 
Glucose (non-fasting) 
Lactate dehydrogenase 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
 
Urine Drug Screen (UDS): 
Opioids 
Cocaine 
Amphetamines 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 
Ethanol 
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; INR = 
international normalized ratio; PT = prothrombin time; and PTT = partial thromboplastin time. 
a 
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to White Blood Cell count, Red Blood Cell 
count, casts and crystals).  
 


 
 
 
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8.5 
Vital Signs 
Vital signs will include SBP, DBP, respiratory rate, heart rate and temperature. Vital signs will 
be measured according to the schedule in APPENDIX A. Triplicate SBP and DBP measurements 
will be done at baseline.  
 
8.6 
Physical Examination Findings 
Physical examination will include date, time and body system examined. Physical examination 
will be performed according to the schedule in APPENDIX A. At screening, previously 
unrecognized findings that are clinically significant will be included as adverse events; other 
clinically significant findings at screening will be included as medical history. After dosing, any 
new or worsening findings will be included as adverse events.  
8.7 
Electrocardiogram 
12-lead ECG includes the parameter ECG mean ventricular rate, PR interval, QRS duration, QT 
interval, QTcF interval and interpretation. 12-lead ECGs will be performed according to the 
schedule in APPENDIX A. Triplicate measurements will be done at baseline. If a potentially 
clinically significant (CS) abnormality is noted during other time points, a triplicate ECG will be 
taken at that time point. 
 
ECG holter monitoring will be recorded on Day 1 from at least 2 hours pre-dose until at least 24 
hours post-dose for Part I and Part II. The continuous 12-lead ECG data will be stored on secure 
digital memory cards for potential transfer to a central ECG laboratory as indicated for QT 
analyses evaluating the risk of prolonged cardiac repolarization. Whether ECG holter monitoring 
was performed, start date/time, and end date/time will be recorded in the eCRF. 
 
 
 
 


 
 
 
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9 DATA HANDLING AND PRESENTATION 
All safety and statistical outputs will be generated using SAS software, version 9.4. 
Pharmacokinetic outputs will be generated using WinNonlin version 8.0 or higher. 
The analyses described in this plan are considered a priori, in that they have been defined prior 
to database lock and/or prior to breaking the blind.  Any analyses performed subsequent to 
database lock and/or breaking the blind that are not described within the present plan will be 
considered post hoc and exploratory.  Post hoc analyses will be labeled as such in the 
corresponding statistical output and identified in the clinical study report (CSR). 
9.1 
Study Population and Safety Analysis Presentation 
Tables of summary statistics will be presented for the Safety population, separately for Part I and 
Part II. For Part I, summaries will be presented by dosing cohort for active treatment and for all 
placebo subjects combined; for Part II, summaries will be presented by period. Summary 
statistics will be number of observations, mean, standard deviation (SD), median, minimum, and 
maximum for continuous variables and counts and percentages for categorical variables. For 
natural log (ln)-transformed endpoints, geometric mean, geometric standard deviation (SD), and 
coefficient of variation (CV%) will also be presented. 
In general, the data listings will include all enrolled subjects and will be presented separately for 
Part I and Part II. Listings will be sorted by cohort (Part I) or period (Part II) and then by subject. 
The following general comments also apply to all statistical analyses and data presentations: 
x Study day is defined as (event date–date of first dose ) + 1 for event dates on or after the 
date of first dose, and as (event date–date of first dose ) for event dates before the first 
dose. For Part II, study day will be defined within period. 
x Duration will be defined as (end date - start date) +1.  
x If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numerical type), 
a coded value must be appropriately determined and used in the statistical analyses.  In 
general, a value or lower and upper limit of normal range such as ‘<10’ or ‘5’ will be 
treated as ‘10’ or ‘5’ respectively, and a value such as ‘>100’ will be treated as ’100’.  
However, the actual values as reported in the database will be presented in data listings. 
x If there are multiple assessments for a given nominal visit or time point, the assessment 
closest in time to the nominal visit or time point will be used in summary tables; if 
assessments are equidistant from the nominal time point, the mean of the assessments 
will be calculated and used in summary tables. Assessments classified as “unscheduled” 
will not be included in summary tables. 
In general, summary statistics for raw variables (i.e., variables measured at the study site or 
central laboratory) will be displayed as follows:  
x Minima and maxima will be displayed to the same number of decimal places as the raw 
data.  
x Means, medians, and quartiles will be displayed to 1additional decimal place.  


 
 
 
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x Standard deviations will be displayed to 2 additional decimal plac
x Percentages will be displayed to 1 decimal place. Percentages between 0 and 0.1 
(exclusive) will be displayed as ‘<0.1’.   
x P-values will be displayed to 3 decimal places. P-values that are less than 0.001 will be 
displayed as ‘<0.001’. 
The numbers of decimal places for summary statistics of derived variables (i.e., variables that are 
not measured by the study site but are calculated for analysis based on other measured variables) 
will be determined on a case by case basis.  In general:  
x Minima and maxima will be displayed to the commonly used unit of precision for the 
parameter.  
x Means, medians, quartiles, and confidence limits will be displayed to 1 additional 
decimal place.  
x Standard deviations will be displayed to 2 additional decimal places. 
 Subject Disposition 
9.1.1
A subject disposition summary will show number of subjects screened, number and percentage 
of screened subjects randomized (Part I) or enrolled (Part II), number and percentage of 
randomized (Part I) or enrolled (Part II) subjects who discontinued the study, and reasons for 
discontinuation with number of discontinued subjects as the denominator. Number and 
percentage of randomized (Part I) or enrolled (Part II) subjects in each analysis population will 
also be summarized. 
Listings of subject disposition and subjects included in each analysis population will be 
provided. A listing showing that each randomized (Part I) and enrolled (Part II) subject met all 
inclusion/exclusion criteria will be provided. Reasons for screen failure will also be listed and 
summarized.  
 Protocol Deviations 
9.1.2
Protocol deviations and PK sampling time deviations will be provided in separate listings. 
Protocol deviation listings will include the deviation description, category, and important/not 
important designation.  
 Demographic and Other Baseline characteristics 
9.1.3
Demographic and other baseline characteristics will be summarized separately for the Safety 
population, PK populations (if different from Safety population), and screen failures. 
 Substance Use Habits 
9.1.4
Alcohol, nicotine and xanthine/caffeine habits will be presented in listings. 
 Medical History 
9.1.5
Any medical history findings will be presented in listings. 


 
 
 
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 Prior Medications 
9.1.6
Prior medications will be presented in listings and will include WHO-DD preferred name, WHO-
DD drug class [anatomic therapeutic chemical (ATC) level 2], start and end date/time, dose, 
route, frequency, and indication. The listing will also include references to related AEs and 
medical history events, if applicable. 
 Childbearing Potential 
9.1.7
Childbearing potential will be presented in a listing (Part I only). 
 Standard High Fat Breakfast 
9.1.8
Standard high fat breakfast will be presented in a listing (Part II only). 
 Adverse event 
9.1.9
For Part I of the study, a TEAE is defined as an AE with start date/time at or after IMP dosing. 
For Part II of the study (a cross-over design): 
A Period 1 (Fasted) TEAE is defined as an AE with start date/time at or after IMP dosing in 
Period 1 and no later than IMP dosing in Period 2.  
A Period 2 (Fed) TEAE is defined as an AE with start date/time at or after IMP dosing in Period 
2 and within the period of time equal to the interval from Period 1 dosing to Period 2 dosing.  
The number and percentage of subjects reporting TEAEs and number of TEAEs will be 
presented both overall and by MedDRA SOC and PT, each in descending order of frequency 
(then alphabetically in case of ties). Separate summaries will be done for IMP-related TEAEs, 
treatment-emergent SAEs (TESAEs), and IMP-related TESAEs. TEAEs will also be summarized 
by maximum severity and by maximum toxicity grade within SOC and PT (refer to APPENDIX 
3 – Tables for Laboratory Abnormalities for events with toxicity grades determined by the 
protocol); i.e., if more than one TEAE is coded to the same PT for the same subject, the subject 
will be counted only once for that PT using the most severe event for the summary by maximum 
severity, and using the most toxic event for the summary by maximum toxicity.  
An overall summary table of TEAEs will be provided that shows incidence and number of events 
for each of the following: 
x Any TEAE 
x IMP-related TEAE 
x TESAE 
x IMP-related TESAE 
x Severe TEAE 
x TEAE with grade 3 or higher toxicity 
x TEAE with outcome of study discontinuation 
x Fatal TEAE 
If any component of an AE starts date/time is missing such that it cannot be determined whether 
or not the AE was treatment-emergent, it will be counted in summaries as treatment-emergent. In 
summaries by relationship to IMP and severity, missing relationship will be summarized as 
“related” and missing severity will be summarized as “severe.” 


 
 
 
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Separate listings will be presented for TEAEs, TESAEs, TEAEs with outcome of study 
discontinuation, fatal TEAEs, and non-TEAEs. 
 Concomitant medication 
9.1.10
Concomitant medication listings will include the medication name, WHO-DD preferred name, 
WHO-DD drug class (ATC level 2), start and end date/time, dose, route, frequency, and 
indication will be presented. The listing will also include references to related AEs and medical 
history events, if applicable. 
 IMP Exposure 
9.1.11
Details of IMP administration of each subject will be presented in listings.  
 Clinical Laboratory Evaluations 
9.1.12
Laboratory data will be presented using units as reported by the clinical laboratory. 
Listings for each category of laboratory test [hematology, serum chemistry, urinalysis, serology, 
coagulation, urine drug screen and other laboratory tests (pregnancy and endocrinology)] will 
include test name, study visit, date and time of specimen collection, reference range, observed 
value, and alert flag. Separate listings will be done for abnormal on-study laboratory values and 
for CS on-study laboratory values. 
Observed values and changes from baseline will be summarized by visit. Shifts from baseline 
will also be summarized. 
 Vital Signs 
9.1.13
Listings will include study visit, date and time of measurement, and observed value. For baseline 
SBP and DBP, triplicate measurements as well as the mean of the triplicate measurements will 
be listed. Separate listings will be done for abnormal on-study vital sign values and for CS on-
study vital sign values. 
Observed values and changes from baseline will be summarized by visit and time point. Baseline 
SBP and DBP will be defined as the mean of the triplicate measurements.  
    
Triplicate means will be programmatically calculated and will be calculated even if there are 
only 1 or 2 measurements available. Triplicate means will be rounded to the nearest integer. 
 
 Physical Examination Findings 
9.1.14
Listings of general physical examination records and CS physical examination findings will be 
presented.  
 Electrocardiogram 
9.1.15
Listings will include study visit, date and time of measurement, and observed value. Triplicate 
measurements as well as the mean of the triplicate measurements will be listed. A separate listing 
will be done for CS on-study ECGs. 
 


 
 
 
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Observed values and, for numeric parameters, changes from baseline will be summarized by visit 
and time point. Means of triplicate measurements will be summarized for numeric results. ECG 
interpretation will be summarized by visit, timepoint, and ECG readings.    
For numeric parameters, triplicate means will be programmatically calculated and will be 
calculated even if there are only 1 or 2 measurements available. Triplicate means will be rounded 
to the nearest integer. For ECG interpretation, if at least 2 of the 3 assessments are the same 
value, the triplicate summary (analogous to the mean for numeric parameters) will be set to this 
value; however, if each assessment is different (eg, “normal,” “abnormal NCS,” and “abnormal 
CS”), the Sponsor will be notified and will provide a value for the triplicate summary of 
interpretation based on a review of the data. 
An ECG holter monitoring listing will include assessment performed, start date/time and end 
date/time. 
 
 
 
9.2 
Analysis Timepoints  
For Part I, the baseline value will be defined as the last non-missing evaluation prior to the first 
dose of IMP. For Part II, the period-specific baseline value will be the last non-missing 
evaluation prior to the first period-specific dose of IMP. If multiple measurements are collected 
at baseline with the same assessment time (or date if time is not available) then the mean of the 
measurements will be taken. All other analysis time points will be based on nominal visits. 
9.3 
Methods for Handling Missing Data  
No imputations of values for missing data (ie, blank, “Not Done”, “Not Applicable”, etc) will be 
performed and data presentations will reflect the data point as it appears in the case report form 
(CRF) or electronic data file.  


 
 
 
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10 INTERIM ANALYSES AND DATA SAFETY MONI
In Part I, there will be a review of safety data for the sentinel group in each cohort before 
proceeding to the next subject in the cohort. There will also be a review of the safety and PK data 
for each cohort before dose escalation. The safety data review will be conducted by the DRSC 
using stopping rules defined in Section 3.6.2.  
PK parameter estimation for safety review will be performed using bioanalytical data applied 
with subject aliases in order to maintain the study blind. PK analysis will be performed using 
nominal time points. The preliminary PK results of INDV-2000 and M12 at the time of the 
safety review will be performed as outlined in Section 7, with the exception that nominal times 
will be used in the analysis instead of actual times. Mean concentration-time profiles as well as 
parameter summary tables of the key PK parameters (e.g. Cmax, Tmax, and AUCs) will be 
generated. 
 PK data will not be part of the safety review. 
No safety review will be performed for Part II.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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11 CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
 
Protocol: 
SAP: 
The number and percentage of subjects 
reporting TEAEs will be presented overall, by 
MedDRA system organ class (SOC) and 
preferred term (PT), each in descending order 
of frequency (then alphabetically in case of 
ties). 
Sentence changed to:  
 
The number and percentage of subjects 
reporting TEAEs (incidence) and number of 
TEAEs will be presented both overall and by 
MedDRA SOC and PT, each in descending 
order of frequency (then alphabetically in case 
of ties). 
IMP-related TEAEs, treatment-emergent 
SAEs (TESAEs), IMP-related TESAEs, 
TEAEs 
leading to death, TEAEs leading to IMP 
discontinuation, and TEAEs leading to IMP 
interruption will be presented both overall and 
by SOC and PT. 
TEAEs leading to death, TEAEs leading to 
IMP discontinuation, and TEAEs leading to 
IMP interruption will be listed but not 
summarized. 
TEAEs will also be summarized by intensity 
within SOC and PT. 
Sentence changed to: 
 
TEAEs will also be summarized by maximum 
severity and by maximum toxicity grade 
within SOC and PT 
In addition, TEAEs leading to death and IMP-
related TEAEs leading to death will be 
summarized separately by PT 
Removed. 
 
Added: 
 
Shifts from baseline in clinically abnormal 
results will also be summarized. 
Concomitant therapies (medications) will be 
collected from screening until the EOS visit 
or the ET visit… 
Concomitant medications are defined as 
medications taken at or after the time of first 
IMP dose. 
The PK analysis population is defined as 
subjects who received at least one dose of 
INDV-2000 and have an adequate number of 
PK samples collected to derive PK 
parameters. 
Sentence changed to :  
The PK population is defined as subjects who 
received at least one dose of INDV-2000 and 
have an adequate number of PK samples 
collected to derive at least one PK parameter.  
 
Added: 
 
The Food Effect PK population will be defined 
as the subset of Part II subjects in the PK 
population that have at least one evaluable PK 
parameter for at least one meal condition. 


 
 
 
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12 GENERAL INFORMATION RELATED TO DATA PRESENTATIONS 
The formats and layouts of TFLs are provided in a separate document and are common displays.  
Their numbering and general content follow the International Conference on Harmonisation 
(ICH) E3 guidelines.  Actual formats and layouts may be altered slightly from those presented as 
necessary to accommodate actual data or statistics.  Minor format changes will not require 
updates to the SAP, rather they may be documented in a Note to SAP. 


 
 
 
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13 REFERENCES 
Not applicable 
 


 
 
 
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APPENDIX A STUDY SCHEDULE(S) 
APPENDIX 1 – Schedule of Events Part I 
Evaluation 
Screening Days 
 -28 to -1 
 
In clinical unit 
Follow-up 
Day -112 
Day 1 
Day 2 
Day 3 
Day 4 
Day 11/EOS10/ET 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics (Includes height, 
weight and BMI) 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination1 
X 
X 
 
X 
 
X 
X 
Urine Drug Screen 
X 
X 
 
 
 
 
 
Alcohol test 
X 
X13 
 
 
 
 
 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
 
X 
 
 
 
 
X 
Urinalysis 
X 
X 
 
X 
 
 
 
FSH test (for post-menopausal 
women only) 
X 
 
 
 
 
 
 
Clinical Laboratory Assessments 
(Chemistry and Hematology) 
X 
X 
 
X 
 
X 
X 
Serology (HIV, Hepatitis B and C) 
X 
 
 
 
 
 
 
Coagulation Panel (PT/INR) 
X 
 
 
 
 
 
 
Vital Signs2 
X 
X 
X2 
X 
 
X 
X 
12-Lead Electrocardiogram3,4 
X3 
X 
X4 
X 
 
X 
X 
26 Hour Holter Monitoring5 
 
 
X 
 
 
 
 
PK Sampling  
 
 
X  
X 
X 
X 
 


 
 
 
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Evaluation 
Screening Days 
 -28 to -1 
 
In clinical unit 
Follow-up 
Day -112 
Day 1 
Day 2 
Day 3 
Day 4 
Day 11/EOS10/ET 
Drug Administration  
 
 
X 
 
 
 
 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
Concomitant Medication Assessment 
X 
X 
X 
X 
X 
X 
X 
Admission to Clinical Unit 
 
X 
 
 
 
 
 
Discharge from Clinical Unit 
 
 
 
 
 
X 
 






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APPENDIX 3 – Tables for Laboratory Abnormalities
Serum *
Mild (Grade 1)
Moderate 
(Grade 2)
Severe (Grade 3)
Potentially Life
Threatening 
(Grade 4)**
Sodium – Hyponatremia mEq/L
132 – 134
130 – 131
125 – 129
< 125
Sodium – Hypernatremia mEq/L
144 – 145
146 – 147
148 – 150
> 150
Potassium – Hyperkalemia mEq/L
5.1 – 5.2
5.3 – 5.4
5.5 – 5.6
> 5.6
Potassium – Hypokalemia mEq/L
3.5 – 3.6
3.3 – 3.4
3.1 – 3.2
< 3.1
Glucose – Hypoglycemia mg/dL
65 – 69
55 – 64
45 – 54
< 45
Glucose – Hyperglycemia Fasting –
mg/dL
Random – mg/dL
100 – 110
110 – 125
111 – 125
126 – 200
>125
>200
Insulin requirements 
or hyperosmolar
coma
Blood Urea Nitrogen
BUN mg/dL
23 – 26
27 – 31
> 31
Requires
dialysis
Creatinine – mg/dL
1.5 – 1.7
1.8 – 2.0
2.1 – 2.5
> 2.5 or requires 
dialysis
Calcium – hypocalcemia mg/dL
8.0 – 8.4
7.5 – 7.9
7.0 – 7.4
< 7.0
Calcium – hypercalcemia mg/dL
10.5 – 11.0
11.1 – 11.5
11.6 – 12.0
> 12.0
Magnesium – hypomagnesemia mg/dL
1.3 – 1.5
1.1 – 1.2
0.9 – 1.0
< 0.9
Phosphorous – hypophosphatemia
mg/dL
2.3 – 2.5
2.0 – 2.2
1.6 – 1.9
< 1.6
CPK – mg/dL
1.25 – 1.5 x
ULN***
1.6 – 3.0 x ULN
3.1 –10 x ULN
> 10 x ULN
Albumin – Hypoalbuminemia g/dL
2.8 – 3.1
2.5 – 2.7
< 2.5
--
Total Protein – Hypoproteinemia g/dL
5.5 – 6.0
5.0 – 5.4
< 5.0
--
Alkaline phosphate –
increase by factor
1.1 – 2.0 x ULN
2.1 – 3.0 x ULN
– 10 x ULN
> 10 x ULN
Liver Function Tests –ALT, AST
increase by factor
1.1 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10 x ULN
> 10 x ULN
Bilirubin – when accompanied
by any increase in Liver Function Test increase 
by factor
1.1 – 1.25 x ULN
1.26 – 1.5 x ULN
1.51 – 1.75 x ULN
> 1.75 x ULN
Bilirubin – when Liver Function Test
is normal; increase by factor
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.0 – 3.0 x ULN
> 3.0 x ULN


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Cholesterol
201 – 210
211 – 225
> 226
Pancreatic enzymes – amylase, lipase
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 5.0 x ULN
> 5.0 x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges 
should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory abnormalities as Potentially Life 
Threatening (Grade 4). For example. a low sodium value that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia 
event if the subject had a new seizure associated with the low sodium value.
***ULN” is the upper limit of the normal range.
Hematology *
Mild (Grade 1)
Moderate (Grade 
2)
Severe (Grade 3)
Potentially Life 
Threatening
(Grade 4)
Hemoglobin (Female) - gm/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female)
change from baseline value - gm/dL
Any decrease – 1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
Hemoglobin (Male) - gm/dL
12.5 – 13.5
10.5 – 12.4
8.5 – 10.4
< 8.5
Hemoglobin (Male)
change from baseline value – gm/dL
Any decrease – 1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
WBC Increase - cell/mm3
10,800 – 15,000
15,001 – 20,000
20,001 – 25, 000
> 25,000
WBC Decrease - cell/mm3
2,500 – 3,500
1,500 – 2,499
1,000 – 1,499
< 1,000
Lymphocytes Decrease - cell/mm3
750 – 1,000
500 – 749
250 – 499
< 250
Neutrophils Decrease - cell/mm3
1,500 – 2,000
1,000 – 1,499
500 – 999
< 500
Eosinophils - cell/mm3
650 – 1500
1501 - 5000
> 5000
Hypereosinophilic
Platelets Decreased - cell/mm3
125,000 – 140,000
100,000 – 124,000
25,000 – 99,000
< 25,000
PT – increase by factor
(prothrombin time)
1.0 – 1.10 x
ULN**
– 1.20 x ULN
1.21 – 1.25 x ULN
> 1.25 ULN
PTT – increase by factor (partial 
thromboplastin time)
1.0 – 1.2 x ULN
1.21 – 1.4 x ULN
1.41 – 1.5 x ULN
> 1.5 x ULN
Fibrinogen increase - mg/dL
400 – 500
501 – 600
> 600
--
Fibrinogen decrease - mg/dL
150 – 200
125 – 149
100 – 124
< 100 or associated with 
gross bleeding or 
disseminated 
intravascular
coagulation (DIC)
*
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference 
ranges should be provided to demonstrate that they are appropriate.
** “ULN” is the upper limit of the normal range.


 
 
 
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Urine * 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or 
dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
Blood (microscopic) – red 
blood cells per 
high power field (rbc/hpf) 
1 - 10 
11 – 50 
> 50 and/or gross 
blood 
Hospitalization or 
packed red blood cells 
(PRBC) 
transfusion 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges 
should be provided to demonstrate that they are appropriate. 
 
 
 
 
 
 

Prot_001.pdf: 
CLINICAL STUDY PROTOCOL: INDV-2000-101 
 
Protocol Title:  A Phase I, Double-blind, Placebo-controlled, 
Randomized, Single Ascending Dose Study to Assess the 
Safety, Tolerability and Pharmacokinetics of INDV-2000 
(C4X_3256) under Fasting and Fed Conditions in Healthy 
Volunteers 
 
Protocol Number: INDV-2000-101 
 
Original Protocol Date: 09 January 2020 
Amendment Number/Date: Amendment 2/ 10 December 2020 
 
NCT: NCT04413552 
 








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INDV-2000-101: A Phase I, Double-blind, Placebo-controlled, 
Randomized, Single Ascending Dose Study to Assess the Safety, 
Tolerability and Pharmacokinetics of INDV-2000 (C4X_3256) under 
Fasting and Fed Conditions in Healthy Volunteers 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to this 
investigational medicinal product (IMP) is the confidential and proprietary information of 
Indivior, and except as may be required by local laws or regulation, may not be disclosed to 
others without prior written permission of Indivior. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. My staff and/or I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
International Council on Harmonisation E6 / Good Clinical Practice guidelines and will make a 
reasonable effort to complete the study within the time designated. 
I agree to ensure all associates, colleagues and employees delegated to assist with the conduct of 
the study are trained on this study protocol and amendments, other study-related materials and 
are qualified to perform their delegated tasks. I will provide all study personnel copies of the 
protocol and any amendments and grant access to all information provided by Indivior or 
specified designees. I will discuss the material with them to ensure that they are fully informed 
about the IMP and appropriate information throughout the study. Mechanisms are in place to 
ensure that site staff receives the appropriate information throughout the study. 
 
 
Signed: 
 
 
Date:  
 
DD-MMM-YYYY 
 
Printed Name 
and Credentials: 
 
Title: 
 
Site Name: 
 
Telephone: 
 
Address: 
 
 
 










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STUDY SCHEMATIC 
Figure 1 
 
Proposed Study Schematic- Part I and II 
 
 
a=active, p=placebo, HV=healthy volunteers; SAD=Single ascending dose 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL: INDV-2000-101 ......................................................1 
CLINICAL PROTOCOL SIGNATURE PAGE .............................................................2 
STUDY PERSONNEL INFORMATION ........................................................................3 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...................................4 
SYNOPSIS ..........................................................................................................................5 
STUDY SCHEMATIC ......................................................................................................9 
TABLE OF CONTENTS ................................................................................................10 
LIST OF IN-TEXT TABLES .........................................................................................13 
LIST OF IN-TEXT FIGURES .......................................................................................13 
LIST OF ABBREVIATIONS .........................................................................................14 
1 
INTRODUCTION AND RATIONALE .................................................................16 
1.1 
Background and Introduction ............................................................................16 
1.2 
Study Rationale ....................................................................................................16 
1.3 
Dose Rationale ......................................................................................................17 
1.4 
Pharmacokinetics (PK) ........................................................................................18 
1.5 
Nonclinical Pharmacology...................................................................................18 
1.6 
Risk-Benefit Assessment ......................................................................................19 
1.7 
Benefit Assessment ...............................................................................................19 
2 
STUDY OBJECTIVES ............................................................................................20 
2.1 
Primary .................................................................................................................20 
2.2 
Secondary..............................................................................................................20 
3 
STUDY ENDPOINTS ..............................................................................................21 
3.1 
Primary .................................................................................................................21 
3.2 
Secondary..............................................................................................................21 
3.3 
Exploratory Endpoints ........................................................................................21 
4 
STUDY PLAN ...........................................................................................................22 
4.1 
Study Design .........................................................................................................22 
4.2 
Schedule of Events ...............................................................................................22 
4.3 
Duration of Treatment ........................................................................................23 
5 
STUDY POPULATION SELECTION ...................................................................24 
5.1 
Number of Subjects..............................................................................................24 
5.2 
Inclusion Criteria .................................................................................................24 
5.3 
Exclusion Criteria ................................................................................................25 
5.4 
Day -1 Check-In Criteria.....................................................................................26 
5.5 
Deviation from Inclusion/Exclusion Criteria ....................................................27 
6 
STUDY CONDUCT..................................................................................................28 
6.1 
Subject Enrollment ..............................................................................................28 
6.2 
Screen Failure.......................................................................................................28 
6.3 
Subject Completion ..............................................................................................28 
6.4 
Dose Escalation and Stopping Criteria ..............................................................28 
6.4.1 
Dose Escalation Criteria ................................................................................28 
6.5 
Subject Withdrawal from the Study ..................................................................29 
6.5.1 
Subject Withdrawal of Consent ....................................................................30 
6.5.2 
Subjects Lost to Follow-up ............................................................................30 
7 
STUDY SUSPENSION OR TERMINATION .......................................................31 






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22.2 
APPENDIX 2 – Schedule of Events Part II .......................................................71 
22.3 
APPENDIX 3 – Liver Safety ...............................................................................74 
22.4 
APPENDIX 4 –Pharmacokinetic Sampling Windows......................................77 
22.5 
APPENDIX 5- Example of High-Fat Meal ........................................................79 
22.6 
APPENDIX 6- Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials .............................80 
I. 
INTRODUCTION................................................................................................82 
II. 
BACKGROUND ..................................................................................................83 
III. 
TOXICITY GRADING SCALE TABLES ........................................................83 
IV. 
REFERENCES .....................................................................................................89 
 
List of In-Text Tables 
Table 1 
List of Laboratory Tests ..........................................................................34 
Table 2 
Part 1 Single Ascending Dose IMP Dosing ............................................42 
 
List of In-Text Figures 
Figure 1 
 Proposed Study Schematic- Part I and II ...............................................9 
 


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List of Abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
BMI 
Area under the plasma drug concentration versus time curve 
Body mass index 
Cmax 
CNS 
Maximum concentration 
Central Nervous System 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CYP 
Cytochrome P450  
DBP 
Diastolic blood pressure 
DRSC 
Data Review and Safety Committee 
ECG 
Electrocardiogram 
eCRF 
EOS 
ET 
Electronic Case Report Form 
End of Study 
Early Termination 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface Antigen 
hERG 
HIV 
Human Ether-a-Go-go Related Gene 
Human immunosufficiency virus 
IB 
Investigator Brochure 
IC50 
Half-maximal inhibitory concentration 
ICF 
Informed Consent 
ICH 
ID 
International Committee on Harmonisation 
Identification 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
LC 
Locus coeruleus 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum well-tolerated 
NOAEL 
No Observed Adverse Effect Level 
OUD 
Opioid use disorder 
OX1 
Orexin-1 
OX2 
Orexin-2 
OX1R 
Orexin-1 receptor 
OX2R 
Orexin-2 receptor 
PD 
PI 
Pharmacodynamic(s) 
Principal Investigator 
pIC50 
Negative log of IC50 


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PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
QTcF 
QT interval corrected with Fridericia’s formula 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SOC 
System Organ Class 
SOP 
Standary Operating Procedures 
SUSAR 
Suspected unexpected serious adverse reaction 
T½ 
Elimination half-life 
Tmax 
Time to reach maximum (peak) plasma concentration following drug 
administration 
TEAE 
Treatment-Emergent Adverse Events 
TESAE 
UDS 
ULN 
Treatment-Emergent Serious Adverse Events 
Urine drug screen 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
















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4.3 
Duration of Treatment 
Part I: The study will be a SAD study with subjects admitting to the clinic on Day -1, and dosing 
on Day 1, followed by a residential period that concludes on Day 4 after assessments are 
completed, except in cases where the residence is extended due to safety concerns determined by 
the Investigator in consultation with the study Medical Monitor. An EOS visit will be performed 
7 days after discharge from the in-patient unit (Day 11). The time from Screening to the EOS 
Visit is 39 days per cohort in Part I, inclusive of the Screening window. 
Part II: The study will be a cross-over, single-dose study with 2 treatment periods. Admission 
will occur on Day -1, followed by dosing (Day 1), and a washout period of at least 1 week or at 
least 5 half-lives between dosing, whichever period is longer. The duration of the washout period 
could be adapted based on the review of PK data of INDV-2000. Subjects will be discharged on 
Day 2 unless tolerability from Part I indicates a longer stay is warranted. If that is the case, 
subjects will stay in the clinical unit until Day 4. If discharged on Day 2, subjects will return to 
the clinical unit on the morning of Day 3 and Day 4 for PK testing. Depending on PK results 
from Part I, the visit schedule may be modified. An EOS visit will be performed on Day 10 of 
the last Treatment Period (Part II, Period 2). The time from Screening to the EOS Visit is 
approximately 45 days, inclusive of the Screening window. 


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5 STUDY POPULATION SELECTION 
5.1 
Number of Subjects 
A sufficient number of subjects will be screened to enroll up to 80 subjects in Part I and Part II. 
Part I: There will be up to 9 planned cohorts of male and non-childbearing potential female 
subjects. Each of the up to 9 planned cohorts will be composed of 8 subjects (6 receiving active 
and 2 placebo). Additional cohorts may be included but predicted exposures will not exceed the 
maximum exposure limits defined. Up to 72 male and female subjects will be enrolled in Part I. 
Part II: Up to 8 male subjects will receive INDV-2000 on 2 occasions separated by a 1-week 
washout period or at least 5 half-lives whichever period is longer, once under fasting conditions 
and once after a standard high-fat breakfast. 
5.2 
Inclusion Criteria 
In order to participate in Part I or Part II of the study, subjects must meet the following criteria: 
1. Must be able to verbalize understanding of the consent form, able to provide written 
informed consent, and verbalize willingness to complete study procedures, be able to comply 
with protocol requirements, rules and regulations of study site, and be likely to complete all 
the study interventions. 
2. Must be considered a healthy male or non-child-bearing female for Part I. 
Women of non-childbearing potential are considered women who: 
a. Do not have a uterus, or 
b. Are surgically sterile (example: has undergone complete hysterectomy, bilateral 
oophorectomy, or tubal ligation), or 
c. Have permanent cessation of ovarian function due to ovarian failure or surgical removal 
of the ovaries, or 
d. Are post-menopausal as defined by 12 months or more of spontaneous amenorrhea as 
confirmed by an FSH >30 mIH/mL. 
3. For Part II, must be considered a healthy male who did not participate in Part I who is willing 
to consume a high-fat meal. 
4. Between 18 and 55 years of age inclusive, 
5. Body mass index (BMI) within 18.0 to 32.0 kg/m2, inclusive (minimum weight of at least 
50.0 kg at Screening). 
6. Male subjects who are sexually active with female partners of child-bearing potential must 
use, with their partner, a condom plus an approved method of effective contraception from 
the time of screening until 90 days after the last dose of Investigational Medicinal Product 
(IMP). Additionally, male subjects must agree to not donate sperm during the study and for 
at least 90 days from the last dose of IMP. Effective methods of contraception are: 
a. Combined (oestrogen and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 


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i. oral 
ii. intravaginal 
iii. transdermal 
b. Progestogen-only hormonal contraception: 
i. oral 
ii. injectable/implantable 
iii. intrauterine hormone-releasing system  (IUS) 
c. Implantable intrauterine device (IUD) 
d. Surgical sterilisation (for example, vasectomy or bilateral tubal ligation) 
e. Male condom with spermicidal gel/foam or with female cap or diaphragm (double 
barrier) 
5.3 
Exclusion Criteria 
In order to participate in Part I or Part II, subjects must not meet any of the following criteria: 
1. Have a medical history of clinically significant neurological, cardiovascular, renal, hepatic, 
chronic respiratory or gastrointestinal disease, or psychiatric disorder as judged by an 
Investigator, 
2. Have clinically significant abnormal biochemistry, hematology or urinalysis results as judged 
by an Investigator, 
3. Have a history of narcolepsy or other significant sleep disorders 
4. Have disorders that may interfere with drug absorption, distribution, metabolism and 
excretion (ADME) processes, 
5. Positive test results for human immunosufficiency virus (HIV)-1/HIV-2 Antibodies, 
Hepatitis B surface Antigen (HBsAg) or Hepatitis C Antibody (HCVAb). 
6. Serious cardiac illness or other medical condition including, but not limited to: 
a. Uncontrolled arrhythmias 
b. History of congestive heart failure (CHF) 
c. Myocardial infarction <6 months from receipt of first dose of IMP 
d. Uncontrolled symptomatic angina 
e. Corrected QT value (QTcF) >450 msec for males and >470 msec for females or history 
of prolonged QT syndrome. 
f. Have a blood pressure reading outside of the following range: Systolic <86 or >149 
mmHg; Diastolic <50 or >94 mmHg 
7. Current active hepatic or biliary disease. Subjects with cholecystectomy <90 days prior to 
screening. 
8. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 
unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine). 
9. Positive test result for alcohol and/or drugs of abuse at screening or prior to the first IMP 
administration. 


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10. Current smokers and those who have smoked within the last 90 days. Current users of e-
cigarettes and nicotine replacement products, and those who have used these products within 
the last 90 days. 
11. Concurrent treatment or treatment with an investigational drug within 30 days prior to the 
first dose. 
12. Blood donation of approximately 500 mL within 56 days or plasma donation within 7 days of 
screening. 
13. Subjects who are taking, or have taken, any prescribed or over-the-counter drugs (other than 
2ௗg per day acetaminophen, hormone replacement therapy [HRT], hormonal contraception) 
or herbal remedies in the 14 days before IMP administration. Exceptions may apply on a case 
by case basis if considered not to interfere with the objectives of the study, as agreed by an 
Investigator and Sponsor’s Medical Monitor. 
14. Any consumption of food or drink containing poppy seeds, grapefruit or Seville oranges 
within 7 days prior to the IMP administration 
15. Treatment with any known drugs that are moderate or strong inhibitors/inducers of 
cytochrome P450 (CYP) 3A4 within 30 days prior to first dose of IMP. 
16. Known allergy or hypersensitivity to IMP or its excipients. 
17. Any condition that, in the opinion of an Investigator, would interfere with evaluation of the 
IMP or interpretation of subject safety or study results. 
18. Affiliated with, or a family member of, site staff directly involved in the study, or anyone 
with a financial interest in the outcome of the study. 
19. Subjects who are unable, in the opinion of an Investigator, to comply fully with the study 
requirements. 
5.4 
Day -1 Check-In Criteria 
Upon passing screening and meeting inclusion and not meeting exclusion criteria, the subject 
will present to the clinic on Day -1. 
Part I and Part II (both periods, fasting and fed) 
The following criteria must be met at Day -1 for the subject to be enrolled in the study. 
1. Female subjects must have a negative urine pregnancy test. 
2. Subjects must not have a Corrected QT value (QTcF) >450 msec for males and >470 
msec for females. 
3. Subjects must have a negative result obtained from the urine drug screen (UDS) and the 
alcohol test (urine ethanol). 
a. Subjects who have a positive result for alcohol will be asked to refrain from 
alcohol and return the next day for retest. This may only occur once. 


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If any of these criteria are not met, the subject will not be enrolled and randomized in Part 1, or 
will not be enrolled in Part II, Period 1 – Dosing Under Fasting Conditions, or will not be 
allowed to move forward into Part II – Dosing after High-Fat Content Meal. 
5.5 
Deviation from Inclusion/Exclusion Criteria 
This study is intended to be conducted as described in this protocol. Waivers from inclusion and 
exclusion criteria are not allowed because they have the potential to jeopardize subject safety, the 
scientific integrity of the study or regulatory acceptability of the data. Indivior does not grant 
waivers to the protocol-defined inclusion and exclusion criteria, and strict adherence to these 
criteria as outlined in the protocol is essential. The Principal Investigator (PI), sub-Investigator or 
suitably qualified designee will be responsible for identifying, documenting and reporting all 
deviations, which are defined as isolated occurrences involving a procedure that did not follow 
the study protocol or study-specific procedure. In the event of a major deviation from the 
protocol due to an emergency, accident or mistake (e. g., eligibility or dosing errors), the PI, sub-
Investigator or suitably qualified designee must contact the Indivior Medical Monitor at the 
earliest possible time by telephone. This will allow an early joint decision regarding the subject’s 
continuation in the study. This decision will be documented by the Investigator and the Sponsor. 
Deviations will be reported as required to the Institutional Review Board (IRB) per their 
reporting process and criteria, and in the final study report. 
Protocol deviations will be identified and documented through programmatic checks of study 
data, as well as through review of selected subject data listings prior to database lock. 
 






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 For a subject who discontinues due to an AE, see Section 10.1.1 for follow-up procedures. Any 
subject withdrawn or discontinuing the study after being dosed  will not be replaced. 
Subjects can be withdrawn from the study for the following reasons: 
x Pregnancy 
x Termination of the study 
x Upon the subject’s request (withdrawal of consent) 
x Significant deviation from the protocol 
x Concurrent illness or requirement for prohibited medication 
x At the discretion of the Investigator 
6.5.1 
Subject Withdrawal of Consent 
If a subject withdraws consent, the subject will not receive any additional doses of study drug in 
Part II. However, the subject may be offered additional tests as needed to monitor their safety 
(e.g., EOS safety assessments or procedures). 
6.5.2 
Subjects Lost to Follow-up 
In cases of a missed visit, the Investigator or designee must attempt to contact the subject and re-
schedule as soon as possible. The Investigator or designee must counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether or not the subject 
wishes to and/or should continue in the study. 
In the event a subject is lost to follow-up, the Investigator or designee must make a reasonable 
effort to contact the subject. Two documented attempts (e. g., phone, email, etc.) to contact the 
subject followed by a certified mailed letter is considered reasonable. 
For the purpose of documenting date of discontinuation for a subject confirmed to be lost to 
follow-up, the date of discontinuation should be the date of last contact with the subject. 
In the case where a certified letter is sent but not confirmed as received by the subject, the date of 
discontinuation is the date the certified letter was sent. 
In the case where a certified letter is sent and has been confirmed as received by the subject, the 
date of discontinuation is the date of the confirmed subject receipt. 
In the event that neither of these above cases applies (which should be explained in the source 
documents), the date of discontinuation is the date of the subject's last study visit. 
 


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7 STUDY SUSPENSION OR TERMINATION 
Indivior reserves the right to temporarily suspend and/or permanently discontinue the study at 
any time and for any reason, including safety or ethical concerns or severe noncompliance. If 
such action is taken, Indivior will discuss the rationale for the decision with the PI. In cases 
where a study is suspended or terminated for safety reasons, Indivior will promptly inform 
Investigators and the Regulatory Authorities of this action and the reason(s) for the suspension or 
termination. 
If required by applicable regulations, the Investigator must inform the IRB promptly and provide 
the reason(s) for the suspension or termination. If the study is prematurely discontinued, all study 
data and drug substance remaining on-site will be returned to Indivior or its designated 
representative. 
 
























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No food will be allowed for at least 4 hours post-dose administration. Water is allowed as 
desired except for at least 1 hour before and at least 1 hour after drug administration. 
For the food effect evaluation of Part II, subjects will consume a high-fat meal within 30 minutes 
prior to INDV-2000 administration. The high-fat meal should provide approximately 800 to 
1000 calories, and should derive approximately 150, 250 and 500 to 600 calories from protein, 
carbohydrate and fat, respectively. Examples of an appropriate high-fat meal are provided in 
Secition 22.5, Appendix 5. Subjects should consume the entire meal in 30 minutes or less; 
however, the dose must be administered 30 minutes after the start of the meal. If the subject 
cannot complete the meal, the approximate percentage of the meal consumed should be recorded 
in the eCRF and continue with the study. Additionally, the start and finish time of the meal will 
be recorded in the eCRF. INDV-2000 will be administered with 240 mL (8 ounces) of water. No 
food will be allowed for at least 4 hours post-dose administration. Water is allowed as desired 
except for at least 1 hour before and at least 1 hour after drug administration. 
Lunch will be provided at least 4 hr post- INDV-2000 (or - placebo) dose for both parts. 
9.4 
Accountability 
The Investigator is responsible for ensuring that all drug substance and study drug is inventoried, 
accounted for and documented in accurate accountability records. Upon completion of the study 
and/or as requested by Indivior, copies of study drug and drug substance accountability records 
will be provided to Indivior. After the monitor completes reconciliation, all unused study drug 
will be destroyed by the Investigator, as per local standard operating procedures (SOP), after 
Indivior has approved the commencement of destruction. All unused drug substance and 
requested retain samples will be maintained at appropriate storage conditions and shipped 
according to the details in the Pharmacy Manual. The IMP must be handled strictly in 
accordance with the protocol, handling guidelines and the label; it must be stored in a locked, 
limited-access area under appropriate environmental conditions. 
Subject level dispensation of IMP must be documented on the appropriate subject level 
accountability form. All IMP dispensation will be performed by a pharmacist or designee, 
checked by a study site staff member and documented on a drug dispensation form. 
Used IMP bottles (for both powder in solution and capsule), and unused IMP must be available 
for verification by the site monitor during monitoring visits. 
9.5 
Reporting Product Complaints 
The Investigator and study site staff are responsible for prompt reporting of product quality 
complaints to Indivior. A product complaint is any concern pertaining to the preparation or 
quality of the drug substance or IMP, and includes, but is not limited to, broken capsules, 
labelling defects or packaging defects, IMP that is thought to be ineffective, or has an 
appearance, taste or odour that is outside of what is expected. 




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miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan. 
Cimetidine is an over-the-counter medication that is a weak CYP3A4 inhibitor. 
Indivior or specified designee should be notified if a subject receives any of these medications 
during the study. 
9.6.3 
Lifestyle Restrictions 
9.6.3.1 
Fluid and Food Intake 
Subjects are required to fast a minimum of 8 hours before blood sample collection at screening. 
In accordance with the exclusion criteria, subjects will not be permitted to eat poppy seeds, 
grapefruit or Seville oranges or drink grapefruit juice or Seville orange juice within 7 days prior 
to study drug administration. 
Restrictions for water and food intake related to study drug administration are discussed in 
Section 9.3. 
9.6.3.2 
Subject Activity Restrictions 
While participating in the study, subjects will not be permitted to perform heavy exercise. 
Subjects are asked to refrain from heavy exercise starting 24 hours before IMP administration. 
9.6.3.3 
Caffeine, Alcohol and Tobacco Restrictions 
Subjects will not be permitted to drink caffeine-containing beverages, eat caffeine-containing 
foods or use caffeine-containing products prior to check-in through the EOS visit. 
In addition to 90 days prior to screening, subjects will refrain from smoking and from using e-
cigarettes and nicotine-containing products through the EOS visit. 
Subjects will refrain from drinking alcohol from prior to check-in throughthe EOS visit. 
9.7 
Compliance 
The PI or sub-Investigator may terminate a subject based on the subject’s ability to comply with 
the protocol requirements. 
 
Study drug will be administered by designated qualified study personnel at the clinical facility. 
The PI or sub-Investigator will be present during the administration of study drug. The time and 
duration, the dose delivered and any dosing observations will be recorded in source 
documentation. The PI, sub-Investigator or designated individual will maintain a log of all study 
drugs dispensed and returned. Drug supplies will be inventoried and accounted for throughout 
the study. The clinical site will have access to the Indivior Medical Monitor for any safety events 
that occur. 
 


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10 ADVERSE EVENTS 
The Investigator or designee is responsible for identifying, documenting and reporting events 
that meet the definition of an AE. 
An AE is any untoward medical occurrence in a subject associated with the use of an IMP 
regardless of the presence of a causal relationship to the IMP. An AE can be any unfavourable 
and unintended sign (including an abnormal laboratory finding) symptom or disease (new or 
exacerbated) temporally associated with an IMP, whether or not considered related to the IMP. 
x Events meeting the definition of an AE include: 
x New condition detected after IMP administration even though the AE may have been 
present prior to receiving IMP. 
x Exacerbation of a pre-existing condition (including intensification of a condition and/or 
an increase in frequency). 
x Any abnormal laboratory test results or other safety assessments felt to be clinically 
significant in the opinion of the Investigator (including those that worsen from baseline). 
x Symptoms and/or the clinical sequelae of a suspected interaction or an overdose of either 
IMP or a concomitant medication. 
x Signs, symptoms or the clinical sequelae resulting from special interest conditions (e.g., 
IMP misuse, medication error, IMP withdrawal, etc.). Overdose per se will not be 
reported as an AE/SAE. 
x Symptoms and/or clinical sequelae that resulted in intervention. 
Events that do not meet the definition of an AE include: 
x Medical or surgical procedures; the condition that leads to the procedure is an AE. 
x Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital, hospitalization for elective surgery, hospitalization 
for observation in the absence of an AE). 
x Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.1 Assessment of Adverse Events 
The Investigator is ultimately responsible for assessing and reporting all AEs as outlined in the 
protocol. The assessment and reporting of AEs may be delegated to a medically qualified sub-
Investigator, trained on this study protocol, who is listed on the delegation of authority log. All 


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AEs regardless of treatment group or suspected causal relationship to the IMP will be reported as 
described in this protocol. 
Adverse events should be volunteered by the subject or solicited from the subject using a 
standard statement, obtained from examination of the subject at a site visit, or from observations 
of clinically significant laboratory values or special examination abnormal values. If an event 
assessed by one of the study scales requires intervention, or if in the opinion of the Investigator, 
it is clinically significant, then it will be reported as an AE. 
All AEs are to be assessed and recorded in a timely manner and followed to resolution or until 
the Investigator determines that there is not an anticipated resolution. Each AE is to be 
documented with reference to severity, date of occurrence, duration, treatment and outcome. 
Furthermore, each AE is to be classified as being serious or non-serious. In addition, the 
Investigator must assess whether the AE is IMP-related or not. 
10.1.1 
Time Period for Collecting Adverse Events 
Adverse event monitoring and reporting will begin after the subjects sign the ICF, continue 
throughout the study and include EOS/ET/Follow-up. Subjects will be monitored by the study 
site staff for untoward effects and will be released from the study after the last procedure is 
completed and confirmed that the subject has no residual untoward effects from the IMP that 
may affect safety. Treatment-emergent AEs will be defined events observed after starting 
administration of INDV-2000 or placebo. 
Surgical procedures, planned before enrolment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion. In this case the medical condition should 
be reported in the subject’s medical history. 
Any clinically significant symptoms will be reported as AEs. All AEs and corresponding 
treatment will be recorded in the eCRFs and a summary of all the safety data will be presented in 
the final Clinical Study Report (CSR). Any ongoing AEs will be appropriately followed up until 
resolution or 14 days after EOS/ET. The study site personnel will make every effort to contact 
the subject for a minimum of 2 attempts after which the outcome of the AE will be considered 
ongoingand the subject will be noted in source as  lost to follow-up. 
If a subject experiences the onset of an SAE within 5 days following study completion and in the 
opinion of the Investigator, that SAE is associated with the study drug, it will be followed and 
reported as described in Section 11.2. 
If an SAE occurs that is deemed related to study drug, a PK sample will be taken as soon as 
possible after the event is reported. If possible, an additional sample should be collected when 
the SAE has been resolved. 


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10.1.2 
Assessment of Intensity 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as “serious,” which is based on subject/event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
 
Intensity 
Definition 
Mild 
Causes transient or mild discomfort; no limitation of usual activities; no 
medical intervention required. 
Moderate 
Causes mild to moderate limitation in activity; some limitation of usual 
activities; no or minimal medical intervention or therapy is required.  
Severe 
Causes marked limitation in activity; some assistance is usually required; 
medical intervention or therapy is required; hospitalization is probable.  
For vital sign assessments and clinical laboraty abnormalities considered by the Investigator to 
be an Adverse Event according to Section 10.1.4, the intensitiy of adverse events will be graded 
in accordance with the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (Section 22.6, 
Appendix 6). 
Adverse events with changes in severity should be documented as separate events. 
10.1.3 
Assessment of Causality 
The Investigator or a medically qualified sub-Investigator, trained on this study protocol and 
listed on the delegation of authority log is responsible for determining the AE relationship to the 
IMP. 
The following categories will be used to define the relationship of an AE to the administration of 
the IMP: 
Not Related: 
Data are available to identify a clear alternative cause for the AE other 
than the IMP.  
Related: 
The cause of the AE is related to the IMP and cannot be reasonably 
explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy and/or other interventions).  
A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. The Investigator will 
use clinical judgment to determine the relationship. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors and the temporal relationship of 
the event to the IMP will be considered and investigated. The Investigator will also consult the 


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IB in the determination of his/her assessment. For each AE/SAE the Investigator must document 
in the medical notes that he/she has reviewed the AE/SAE and has provided an assessment of 
causality. 
There may be situations when an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to Indivior or designated representative. However, it is 
imperative that the Investigator always make an assessment of causality for every event prior to 
the initial transmission of the SAE data to Indivior or designated representative. The Investigator 
may change his/her opinion of causality in light of follow-up information and amend the SAE 
data collection tool accordingly. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
10.1.4 
Clinical Laboratory Changes 
Changes in laboratory values, vital signs or other safety parameters (e. g. , neurological and 
clinical symptom assessments) as noted in the protocol are a subset of AEs and are reportable 
only if the lab test result is associated with accompanying symptoms, and/ or requires additional 
diagnostic testing or intervention (medical, surgical), and/or requires additional significant 
treatment, and/or requires temporal or permanent discontinuation of IMP, or a change to dosing 
other than as permitted by protocol, or if considered to be clinically significant by Investigator or 
medically qualified designee. 
Screening laboratory assessments, if determined to be clinically significant by the Investigator, 
are not AEs.  
 


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11 SERIOUS ADVERSE EVENTS 
The Investigator or designee is responsible for identifying, documenting and reporting events 
that meet the definition of an SAE. 
An SAE is any event that meets any of the following criteria: 
x Death 
x Life-threatening 
x In-patient hospitalization or prolongation of existing hospitalization 
x Persistent or significant disability/incapacity 
x Congenital anomaly/birth defect in the offspring of a subject who received INDV-2000 
x Other: Important medical events that may not result in death, be life-threatening or 
require hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
events are: 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias or convulsions that do not result in in-patient hospitalization 
 
Development of IMP abuse or diversion 
x Potential Hy’s Law cases indicative of medication-induced hepatocellular injury, defined 
as: 
o ALT 3x ULN and total bilirubin of 2x ULN (or INR >1. 5 if measured) 
o ALT or AST >3x ULN with systemic symptoms (fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia [>5%]) 
x Potential Hy’s Law cases should be managed as described in Section 22.3, Appendix 3. 
An AE is considered “life-threatening” if the subject was at immediate risk of death from the 
event as it occurred; i.e. , it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, IMP-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though IMP-induced 
hepatitis can be fatal. 
AEs requiring hospitalization should be considered SAEs. Hospitalization for elective surgery or 
routine clinical procedures that are not the result of AE (e. g. , elective surgery for a pre-existing 
condition that has not worsened) should not be considered AEs or SAEs. If anything untoward is 


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reported during the procedure, that occurrence must be reported as an AE (either 'serious' or 
'non-serious') according to the usual criteria. 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or other outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 'hospitalization' occurred 
or was necessary, the AE should be considered serious. 
An AE is incapacitating or disabling if the experience results in a substantial and/or permanent 
disruption of the subject's ability to carry out normal life functions. 
11.1 Documenting Serious Adverse Events 
When an SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory and diagnostic reports) pertaining to the event. The 
Investigator will then record all relevant information regarding the SAE on the appropriate 
electronic or paper form(s). 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to 
Indivior in lieu of completion of the SAE Reporting Form. However, there may be cases where 
copies of medical records are requested by Indivior or designated representative. In this instance, 
all subject identifiers, with the exception of subject number, will be redacted on the copies of the 
medical records prior to submission to Indivior. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms 
and/or other clinical information. In such cases, the diagnosis will be documented as an AE or 
SAE and not the individual signs/symptoms. 
11.2 Reporting Serious Adverse Events 
11.2.1 
Investigator Reporting of Serious Adverse Events 
Once the Investigator determines that an event meets the protocol definition of an SAE, the SAE 
will be reported to Indivior (or designated representative) by the Investigator (or designee) 
within 24 hours from first being aware of the event using the form provided by Indivior or 
designated representative. Any follow-up information on a previously reported SAE will also be 
reported to Indivior within 24 hours. 
Where additional information is needed or expected, the Investigator will not wait to receive all 
information before reporting the event to Indivior. The Investigator must provide an assessment 
of causality at the time of the initial report as described in Section 10.1.3. 
In the event of an SAE, the Investigator or designee will notify both the Indivior Medical 
Monitor at the phone number and/or email address listed under Study Personnel Information and 




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12 PREGNANCY 
Participants will include women of non-childbearing potential and men who agree to use highly 
effective means of contraception. Pregnancy is not anticipated during the conduct of this study. 
In the case where a subject’s routine pregnancy test as required per protocol is positive for 
pregnancy prior to dosing, the subject should not be dosed. If the subject has a positive urine 
pregnancy test, a confirmatory serum pregnancy test should be performed. 
12.1 Action to be Taken if Pregnancy Occurs in a Female Partner 
If the partner of a study subject becomes pregnant, the pregnancy will be reported to the clinical 
unit within 48 hours of the subject’s knowledge of the pregnancy. The Investigator will attempt 
to collect pregnancy information on any female partner of a randomized male study subject who 
becomes pregnant while participating in this study. 
After obtaining the necessary signed informed consent from the female partner directly, the 
Investigator will record pregnancy information on the appropriate form and submit it to Indivior 
or designated representative within 24 hours of learning of the partner’s pregnancy. The partner 
will also be followed to determine the outcome of the pregnancy and information on the status of 
the mother and child will be forwarded to Indivior or designated representative. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
premature termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
 


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13 DATA MANAGEMENT 
13.1 Data Collection and Management 
Data will be entered into the eCRF and will be combined with other data captured centrally 
outside of the eCRF into a validated system. Clinical data will be managed in accordance with 
the data management plan to ensure that the integrity of the data is maintained. Adverse events, 
medical history and indication for concomitant medications will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be coded using 
the World Health Organization (WHO) Drug Dictionary. The eCRFs (including queries and 
audit trails) will be retained by Indivior. An electronic copy of the eCRF will be sent to the 
Investigator for their records. Subject identifiers will not be collected or transmitted to Indivior 
according to Indivior standards and procedures. Data collection will be completed according to 
the study plans. 
13.1.1 
Database Quality Assurance 
The eCRFs will be reviewed and checked for omissions, apparent errors and values requiring 
further clarification using computerized and manual procedures. Data queries requiring 
clarification will be generated and addressed by the investigational site. Only authorized 
personnel will make corrections to the eCRFs, and all corrections will be documented in an audit 
trail. 
13.1.2 
Source Documents 
The Investigator is responsible for the quality of the data recorded in the eCRFs. The data 
recorded should be a complete and accurate account of the subject’s record collected during the 
study. 
Study data are not to be gathered directly onto the eCRF, but must be gathered onto primary 
source documents at the clinical site. Completion of source documents will precede the 
completion of the eCRF. Source documents may be electronic, hard copy, or a combination of 
both and are defined as the results of original observations and activities of a clinical 
investigation. Source documents will include, but are not limited to, progress notes, electronic 
data, screening logs and recorded data from automated instruments. All source documents 
pertaining to this study will be maintained by the Investigator and made available for direct 
inspection by the authorized study personnel outlined in the ICF. The CRF will be considered the 
source document for individual CRF elements such as study-specific scales if those data are 
collected directly onto a CRF. 
 


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14 STATISTICS 
14.1 General Procedures 
This section describes the sample size, analysis populations and planned analyses for PK and 
safety endpoints. A comprehensive statistical analysis plan (SAP) will be developed to detail the 
statistical methodology for all aspects of the planned analyses. The SAP will be approved after 
the protocol is finalized and before the database is locked. Any deviations from the analyses 
described below will be identified in the SAP (and subsequently the CSR). Any unplanned 
analyses not described in the SAP will be identified in the CSR. 
Data will be listed and summarized separately for Parts I and II of the study. For Part I, data will 
be summarized by dosing cohort for active treatment and for all placebo subjects combined. For 
Part II, data will be summarized by treatment group (fed or fasted) where applicable. Continuous 
variables will be summarized using descriptive statistics such as means, standard deviations 
(SD), medians, minimums and maximums. Categorical variables will be reported as frequency 
counts (including number missing) and the percentage of subjects in corresponding categories. 
Individual subject data will be presented by subject in data listings. Data listings will include all 
data collected from screened subjects (i.e., subjects who sign informed consent). 
For change from baseline calculations, baseline will be defined as the last measurement taken 
prior to dosing. 
14.2 Sample Size 
The sample size is not based on formal power calculations because the study is only designed to 
provide initial assessment of the safety, tolerability and PK for INDV-2000. The sample size 
used is typical for studies of this nature and should be adequate to assess the parameters 
described. 
14.3 Analysis Populations 
14.3.1 
Safety Population 
The Safety Population is defined as subjects who received at least one dose of IMP. 
14.3.2 
Pharmacokinetic Population 
The PK analysis population is defined as subjects who received at least one dose of INDV-2000 
and have an adequate number of PK samples collected to derive PK parameters. 
14.3.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics (e.g., sex, race, age, weight, height, BMI) will be 
summarized for the Safety Population and separately for screen failures. 






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14.5 Interim Analysis 
No formal interim analysis is planned. In Part I, there will be a review of safety data for the 
sentinel group in each cohort before proceeding to the next subject in the cohort. There will also 
be a review of the safety and PK data for each cohort before dose escalation. The safety data 
review will be conducted by the DRSC (Section 15.2) using stopping rules defined in Section 
6.4. 
14.6 Handling of Missing Data 
In general, missing data (caused by premature discontinuation or otherwise) will not be imputed. 
14.7 Other Safety Analyses 
Other safety endpoints will be listed and summarized using the Safety Population. Other safety 
endpoints include changes from baseline in clinical laboratory evaluations, vital signs, ECG 
parameters and physical examinations. 
14.8 Extent of Exposure 
Frequency and percentage of subjects dosed in each cohort for Part I and dosed in each 
Fed/Fasted group separately for Part II will be provided. 
14.8.1 
Laboratory Data 
Observed values and changes from baseline in laboratory parameters will be summarized by 
analysis visit. 
Clinically abnormal laboratory results will also be summarized by frequency and percentages for 
each category. 
14.8.2 
Vital Signs 
Observed values and changes from baseline in vital signs (SBP and DBP, respiratory rate, heart 
rate and temperature) will be summarized by analysis visit. 
14.8.3 
Physical Examination 
Clinically significant physical examination findings will be summarized by analysis visit. 
14.8.4 
Electrocardiogram 
Results from 12-lead ECG will be categorized as normal, abnormal not clinically significant, or 
abnormal clinically significant and will be summarized by analysis visit using frequencies and 
percentages for each category. Observed values and changes from baseline in ECG interval 
measurements will also be summarized by analysis visit. 




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informed consent documents are required to have been reviewed and received a favorable 
opinion/approval from an IRB prior to presenting them to a potential subject. 
Any changes to the ICF must be reviewed by Indivior before submission to the IRB. 
The written informed consent process will include the review of oral and written information 
regarding the purpose, methods, anticipated duration and risks involved in study participation. 
The Investigator is to ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided. The Investigator or a person designated by 
the Investigator must also explain to each subject that participation is voluntary, and that consent 
can be withdrawn at any time and without reason. Subjects will receive a signed and dated copy 
of the signed ICF before any study-specific procedures are conducted. 
In the event that new safety information emerges that represents a significant change in the 
risk/benefit assessment, the signed ICF should be updated accordingly. All subjects should be 
informed of the new information, provide their consent to continue in the study, and be provided 
with a signed and dated copy of the revised signed ICF. 
15.5 Records Management 
The Investigator must maintain all study-related records (except for those required by local 
regulation to be maintained elsewhere) in a safe and secure location throughout the conduct and 
following the closure of the study. The records must be accessible upon request (e. g. , for an 
IRB, Indivior or regulatory inspection) along with the facility, study personnel and supporting 
systems/hardware. All documents pertaining to the study, including all versions of the approved 
study protocol, copy of the ICF and other documents as required per local laws and regulations 
(e. g. , Health Insurance Portability and Accountability Act [HIPAA] documents), completed 
CRFs, source records (subject records, subject diaries, hospital records, laboratory records, drug 
accountability records, etc. ), and other study-related materials will be retained in the permanent 
archives of the study site. 
Where permitted by local laws and regulations, records may be maintained in a format other than 
hard copy (e. g. , electronically in an electronic medical records system). The Investigator must 
ensure that all reproductions are an accurate legible copy of the original and that they meet 
necessary accessibility and retrieval standards. The Investigator must also ensure that a quality 
control process is in place for making reproductions and that the process has an acceptable back-
up of any reproductions. 
The minimum retention time for retaining study records will be in accordance with the strictest 
standard applicable for the study site as determined by local laws, regulations or institutional 
requirements. At a minimum, records will be maintained for 25 years. If the Investigator 
withdraws from the study (e. g. , relocation, retirement) all study-related records should be 
transferred, in a written agreement with Indivior, to a mutually agreed upon designee within 
Indivior-specified timeframe. 




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CRFs with source documents. The Investigator agrees to participate with audits conducted at a 
reasonable time in a reasonable manner. Full consultation with the Investigator will be made 
prior to and during such an audit, which will be conducted according to Indivior's or a Contract 
Research Organization's QA SOPs. In addition, this study is subject to inspections by Regulatory 
Authorities. If such a regulatory inspection occurs, the Investigator agrees to allow the regulatory 
inspector direct access to all relevant study documents. The Investigator must contact Indivior 
immediately if this occurs and must fully cooperate with the inspection conducted at a reasonable 
time in a reasonable manner. 
 


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17 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Indivior. A protocol change intended to eliminate an apparent immediate hazard to 
subjects may be implemented immediately, provided the IRB is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB and the Investigator must await approval before 
implementing the changes. Indivior or designated representative will submit protocol 
amendments to the appropriate Regulatory Authorities for approval. 
If in the judgment of the IRB, the Investigator and/or Indivior, the amendment to the protocol 
substantially changes the study design and/or increases the potential risk to the subject and/or has 
an impact on the subject's involvement as a study subject, the currently approved written ICF 
will require similar modification. In such cases, informed consent will be renewed for subjects 
enrolled in the study before continued participation, based on IRB determination. 
 


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18 STUDY REPORTS AND PUBLICATIONS 
A CSR will be prepared following completion of the study. An Investigator signatory may be 
identified for the approval of the report if required by applicable regulatory requirements. 
The study data will be owned by Indivior. Publication of any and all data will be at the discretion 
of Indivior. The Investigator will not disseminate, present or publish any of the study data 
without the prior written approval from Indivior to do so. 
 


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19 STUDY TERMINATION 
Both Indivior and the Investigator reserve the right to terminate the study at the Investigator’s 
site at any time. Should this be necessary, Indivior, or a specified designee will inform the 
appropriate Regulatory Authorities of the termination of the study and the reasons for its 
termination, and the Investigator will inform the IRB of the same. In terminating the study, 
Indivior and the Investigator will assure that adequate consideration is given to the protection of 
the subjects’ interests. 


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20 CONFIDENTIALITY 
All subject-identifying documentation generated in this study is confidential and may not be 
disclosed to any persons not directly concerned with the study without written permission from 
the subject. However, authorized regulatory officials and Indivior personnel (or their 
representatives) will be allowed full access to inspect and copy the records. All subject bodily 
fluids and/or other materials collected shall be used solely in accordance with this protocol and 
the ICF signed by the subject, unless otherwise agreed to in writing by Indivior. 
Each subject will be identified by an assigned subject number when reporting study information 
to any entity outside of the study center. During the blinded portion of the study, if use of the 
subject number could be unblinding, false or ‘dummy’ subject identifiers may be used. Data 
containing subject identification will not be removed from the study center without first 
redacting subject identifiers. 


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CDER, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
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Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe 
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Marcus J. Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK. 
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22.3 APPENDIX 3 – Liver Safety 
 
The following should occur if a subject meets any of the liver chemistry stopping criteria as 
outlined in Section 6.4 of the protocol: 
x Subject should immediately be withdrawn from treatment. Do not re-challenge with study 
treatment. 
x Notify the Indivior Medical Monitor or specified designee within 24 hours of learning of 
the abnormality. 
x Completed the “Safety Follow-up Procedures” listed below. 
x Upon completion of the safety follow-up, the subject must be withdrawn from the study 
unless further follow-up is required. 
Subjects with ALT 3x ULN and bilirubin 2x ULN (>35% direct); or ALT 3x ULN and 
INR >1. 5: 
This event is an SAE and should be reported using the SAE Reporting Form (Section 11). 
Serum bilirubin fractionation should be performed, if testing is available. If fractionation is 
unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, 
which would suggest liver injury). 
Make every reasonable attempt to have the subject return to the clinic within 24 hours for repeat 
liver chemistries, additional testing and close monitoring (with specialist or hepatology 
consultation recommended). 
Monitor the subject twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values. 
Subjects with ALT 5x ULN or ALT 3x ULN who have hepatitis symptoms or rash, 
cannot be monitored for 4 weeks or have elevations that persist 4 weeks: 
x Make every reasonable attempt to have the subject return to the clinic within 24-72 
hours for repeat liver chemistries and additional testing. 
x Monitor subject weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values. 
Subjects with ALT 3x ULN and <5x ULN and bilirubin <2x ULN, who do not exhibit 
hepatitis symptoms or rash: 


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x Contact the Indivior Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety. 
x Subject may continue study treatment, if liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) can be monitored weekly for up to 4 weeks. 
x If the subject later meets the liver chemistry stopping criteria (outlined in  
Section 6.5 of the protocol), immediately withdraw study treatment, perform additional 
testing and continue safety follow-up until liver chemistries resolve, stabilize or return to 
baseline values. 
x After 4 weeks of monitoring, if ALT <3x ULN and bilirubin <2x ULN, subject must be 
monitored twice monthly until liver chemistries normalize or return to within baseline 
values. 
Additional follow-up procedures for subjects who meet any of the stopping criteria: 
x Viral hepatitis serology including: 
x Hepatitis A Immunoglobulin M (IgM) antibody, 
x HBsAg and Hepatitis B Core Antibody (IgM), 
x Hepatitis C RNA, 
x Cytomegalovirus IgM antibody, 
x Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing), and 
x Hepatitis E IgM antibody. 
x Blood sample for PK analysis, obtained within 48 hours of last dose. 
x Serum creatine phosphokinase and lactate dehydrogenase. 
x Fractionate bilirubin, if total bilirubin 2x ULN. 
x Assess eosinophilia. 
x Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia) as relevant on the AE eCRF. 
x Record use of concomitant medications, acetaminophen, herbal remedies, other 
over-the-counter medications or putative hepatotoxins on the Concomitant 
Medications eCRF. 


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x Record alcohol use in the eCRF. 
x In addition, the following are required for subjects with ALT 3x ULN and 
bilirubin 2x ULN (<35% direct) but optional for other abnormal liver 
chemistries: 
x Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies and quantitative total immunoglobulin G 
(IgG or gamma globulins). 
x Serum acetaminophen adduct High-Performance Liquid Chromatography 
(HPLC) assay (quantifies potential acetaminophen contribution to livery 
injury in subjects with definite or likely acetaminophen use in the 
preceding week [ 
x James 2009]). 
x Liver imaging (ultrasound, MRI, or CT) to evaluate liver disease. Data 
should be entered into the eCRF, if these tests are performed. 
 
 






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22.5 APPENDIX 5- Example of High-Fat Meal 
The following is an example of an appropriate high-fat meal to be consumed within 30 minutes 
of INDV-2000 administration in Part II, Period 2 on Day 1 for subjects participating in the food 
effect evaluation. 
Food item a 
Calories 
(kcal) 
Fat  
(g) 
Carbohydrates 
(g) 
Protein  
(g) 
2 eggs, fried 
185 
14. 1 
1. 3 
12. 5 
2 strips bacon, fried 
84 
6. 4 
0. 2 
6. 0 
2 slices of white bread, toasted 
129 
1. 8 
24. 0 
4. 0 
4 ounces of hash brown potatoes 
207 
 
 
 
8 fluid ounces of whole milk 
146 
 
 
 
1 tablespoon butter 
102 
 
 
 
Total grams (g) 
- 
 
 
 
Total Calories (kcal) 
853 
 
 
 
% of Total Calories 
100 
 
 
 
a Substitutions can be made as long as the meal provides a similar amount of calories from protein, 
carbohydrate and fat and has comparable meal volume and viscosity.  


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22.6 APPENDIX 6- Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials 
Guidance for 
Industry 
Toxicity Grading Scale for 
Healthy Adult and 
Adolescent Volunteers 
Enrolled in Preventive 
Vaccine Clinical Trials 
 
 
Additional copies of this guidance are available from the Office of Communication, 
Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, 
Rockville, MD 20852- 1448, or by calling 1-800-835-4709 or 301-827-1800, or from the 
Internet at http://www.fda.gov/cber/guidelines.htm. 
 
For questions on the content of this guidance, contact the Division of Vaccines and 
Related Products Applications, Office of Vaccines Research and Review at 301-827-3070. 
U.S. Department of Health and Human Services 
Food and Drug 
Administration Center for 
Biologics Evaluation and 
Research 
September 2007 


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Table of Contents 
I. 
INTRODUCTION....................................................................................................1 
II. 
BACKGROUND ......................................................................................................2 
III. 
TOXICITY GRADING SCALE TABLES ............................................................2 
A. 
Tables for Clinical Abnormalities ..............................................................3 
B. 
Tables for Laboratory Abnormalities ........................................................6 
IV. 
REFERENCES .........................................................................................................8 




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FDA’s guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. 
The use of the word should in FDA’s guidances means that something is suggested or 
recommended, but not required. 
 
II. 
BACKGROUND 
Standardized toxicity assessment scales have been widely used to evaluate products treating 
specific diseases. For example, the National Cancer Institute’s Common Toxicity Criteria Scale 
and the Division of AIDS’ Toxicity Grading Scale standardize the evaluation of adverse events 
among patients with cancer and HIV/AIDS, respectively (Refs. 1, 2). The defined toxicity 
parameters in those scales are designed for patients who may already experience mild, moderate, 
or severe adverse clinical or laboratory events due to the disease process, and may not be 
appropriate for healthy volunteers. 
In the development of the toxicity grading scales for healthy volunteers, we chose parameter 
limit values based on published information, when such values were available (Refs. 1-6). For 
example, the Brighton Collaboration has developed case definitions and guidelines to evaluate 
some adverse events associated with administering vaccines (Ref. 3). In some cases, parameter 
limit values were based on clinical experience and experience reviewing vaccine clinical trials 
that enroll normal healthy subjects. 
Toxicity grading scales for laboratory abnormalities should consider the local laboratory 
reference values when the parameter limit values are defined. The characterization of laboratory 
parameters among some populations of healthy adults and adolescents may require the exercise 
of clinical judgment, for example, consideration of the potential for ethnic differences in white 
blood cell (WBC) counts or gender differences in creatine phosphokinase (CPK) values. 
III. 
TOXICITY GRADING SCALE TABLES 
Adverse events in a clinical trial of an investigational vaccine must be recorded and monitored 
and, when appropriate, reported to FDA and others involved in an investigation (sponsors, IRBs, 
and investigators). (See, for example, 21 CFR 312.32, 312.33, 312.50, 312.55, 312.56, 312.60, 
312.62, 312.64, 312.66). Although the use of a toxicity grading scale for adverse events would 
not replace these regulatory requirements, using a scale to categorize adverse events observed 
during a clinical trial may assist you in monitoring safety and making required reports. 
Nonetheless, we believe that categorization or grading of data as outlined in this document is 
supplementary to and should not replace full and complete data analysis. 
These guidelines for toxicity grading scales are primarily intended for healthy adult and 
adolescent volunteers. The parameters in the tables below are not necessarily applicable to every 
clinical trial of healthy volunteers. The parameters monitored should be appropriate for the 
specific study vaccine. For some preventive vaccines under development, it may be appropriate 


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to include additional parameters to be monitored during a clinical trial or to alter the choice of 
values in the toxicity table. For example, additional parameters might be added based on one or 
more of the following: safety signals observed in pre-clinical toxicology studies, the biological 
plausibility of the occurrence of certain adverse events, or previous experience with a similar 
licensed product. 
As discussed above, the tables do not represent a recommendation to monitor all the listed 
parameters in all clinical trials of healthy volunteers, nor do the tables represent all possible 
parameters to be monitored. In addition, these tables do not represent study inclusion or 
exclusion criteria. We recommend that the parameters monitored be appropriate for the study 
vaccine administered to healthy volunteers participating in the clinical trial. 
A. 
Tables for Clinical Abnormalities 
Local Reaction to 
Injectable 
Product 
Mild (Grade 1) 
Moderate(Grade 2) Severe (Grade 3) Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not 
interfere with 
activity 
Repeated use of 
non- narcotic pain 
reliever 
> 24 hours or 
interferes 
with activity 
Any use of 
narcotic pain 
reliever or 
prevents 
daily activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort 
with movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Redness * 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling ** 
2.5 – 5 cm and 
does not 
interfere 
with activity 
5.1 – 10 cm 
or interferes 
with 
activity 
> 10 cm or 
prevents 
daily 
activity 
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 


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Vital Signs * 
Mild (Grade 1) 
Moderate(Grade 2) 
Severe (Grade 3) Potentially 
Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
(°F) ** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats 
per minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization 
for 
arrhythmia 
Bradycardia - beats 
per minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) 
- mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization 
for malignant 
hypertension 
Hypertension (diastolic) 
- mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization 
for malignant 
hypertension 
Hypotension (systolic) 
– mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization 
for hypotensive 
shock 
Respiratory Rate – 
breaths 
per minute 
17 – 20 
21 – 25 
> 25 
Intubation 
* Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when characterizing 
bradycardia among some healthy subject populations, for example, conditioned athletes. 


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Systemic (General) 
Mild (Grade 1) 
Moderate(Grade 2) Severe (Grade 3) Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference 
with activity or 1 – 
2 episodes/24 hours 
Some interference 
with activity or > 
2 episodes/24 
hours 
Prevents daily 
activity, 
requires 
outpatient 
IV hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2 – 3 loose stools or 
< 400 gms/24 hours 
4 – 5 stools or 
400 – 800 
gms/24 hours 
6 or more 
watery stools or 
> 800gms/24 
hours or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non- narcotic pain 
reliever > 24 hours or 
some 
interference with 
activity 
Significant; 
any use of 
narcotic pain 
reliever or 
prevents 
daily activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents 
daily activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents 
daily 
activity 
ER visit or 
hospitalization 
 
Systemic Illnes 
Mild (Grade 1) 
(Moderate(Grade 2) Severe (Grade 3) Potentially Life 
Threatening 
(Grade 4) 
Illness or clinical 
adverse event (as 
defined according to 
applicable 
regulations) 
No interference 
with activity 
Some 
interference with 
activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires 
medical 
intervention 
ER visit or 
hospitalization 


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B.
Tables for Laboratory Abnormalities
The laboratory values provided in the tables below serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate.
Serum *
Mild (Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life
Threatening 
(Grade 4)**
Sodium – Hyponatremia mEq/L
132 – 134
130 – 131
125 – 129
< 125
Sodium – Hypernatremia mEq/L
144 – 145
146 – 147
148 – 150
> 150
Potassium – Hyperkalemia mEq/L
5.1 – 5.2
5.3 – 5.4
5.5 – 5.6
> 5.6
Potassium – Hypokalemia mEq/L
3.5 – 3.6
3.3 – 3.4
3.1 – 3.2
< 3.1
Glucose – Hypoglycemia mg/dL
65 – 69
55 – 64
45 – 54
< 45
Glucose –
Hyperglycemia 
Fasting – mg/dL
Random – mg/dL
100 – 110
110 – 125
111 – 125
126 – 200
>125
>200
Insulin 
requirements or 
hyperosmolar
coma
Blood Urea Nitrogen
BUN mg/dL
23 – 26
27 – 31
> 31
Requires
dialysis
Creatinine – mg/dL
1.5 – 1.7
1.8 – 2.0
2.1 – 2.5
> 2.5 or requires 
dialysis
Calcium – hypocalcemia mg/dL
8.0 – 8.4
7.5 – 7.9
7.0 – 7.4
< 7.0
Calcium – hypercalcemia mg/dL
10.5 – 11.0
11.1 – 11.5
11.6 – 12.0
> 12.0
Magnesium – hypomagnesemia 
mg/dL
1.3 – 1.5
1.1 – 1.2
0.9 – 1.0
< 0.9
Phosphorous – hypophosphatemia
mg/dL
2.3 – 2.5
2.0 – 2.2
1.6 – 1.9
< 1.6
CPK – mg/dL
1.25 – 1.5 x
ULN***
1.6 – 3.0 x ULN
3.1 –10 x ULN
> 10 x ULN
Albumin – Hypoalbuminemia g/dL
2.8 – 3.1
2.5 – 2.7
< 2.5
--
Total Protein – Hypoproteinemia 
g/dL
5.5 – 6.0
5.0 – 5.4
< 5.0
--
Alkaline phosphate –
increase by factor
1.1 – 2.0 x ULN
2.1 – 3.0 x ULN
3.1 – 10 x ULN
> 10 x ULN
Liver Function Tests –ALT, AST
increase by factor
1.1 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10 x ULN
> 10 x ULN
Bilirubin – when accompanied
by any increase in Liver Function 
Test increase by factor
1.1 – 1.25 x 
ULN
1.26 – 1.5 x ULN
1.51 – 1.75 x 
ULN
> 1.75 x ULN
Bilirubin – when Liver Function 
Test
is normal; increase by factor
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.0 – 3.0 x ULN
> 3.0 x ULN
Cholesterol
201 – 210
211 – 225
> 226
---
Pancreatic enzymes – amylase, 
lipase
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 5.0 x ULN
> 5.0 x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls 
within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if the subject 
had a new seizure associated with the low sodium value.
***ULN” is the upper limit of the normal range.


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Hematology *
Mild (Grade 1)
Moderate 
(Grade 2)
Severe (Grade 
3)
Potentially 
Life 
Threatening
(Grade 4)
Hemoglobin (Female) - gm/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female)
change from baseline value -
gm/dL
Any decrease –
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
Hemoglobin (Male) - gm/dL
12.5 – 13.5
10.5 – 12.4
8.5 – 10.4
< 8.5
Hemoglobin (Male)
change from baseline value –
gm/dL
Any decrease –
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
WBC Increase - cell/mm3
10,800 – 15,000
15,001 – 20,000
20,001 – 25, 000
> 25,000
WBC Decrease - cell/mm3
2,500 – 3,500
1,500 – 2,499
1,000 – 1,499
< 1,000
Lymphocytes Decrease -
cell/mm3
750 – 1,000
500 – 749
250 – 499
< 250
Neutrophils Decrease - cell/mm3
1,500 – 2,000
1,000 – 1,499
500 – 999
< 500
Eosinophils - cell/mm3
650 – 1500
1501 - 5000
> 5000
Hypereosinophilic
Platelets Decreased - cell/mm3
125,000 –
140,000
100,000 – 124,000
25,000 – 99,000
< 25,000
PT – increase by factor
(prothrombin time)
1.0 – 1.10 x
ULN**
1.11 – 1.20 x ULN 1.21 – 1.25 x 
ULN
> 1.25 ULN
PTT – increase by 
factor (partial 
thromboplastin time)
1.0 – 1.2 x ULN
1.21 – 1.4 x ULN
1.41 – 1.5 x ULN > 1.5 x ULN
Fibrinogen increase - mg/dL
400 – 500
501 – 600
> 600
--
Fibrinogen decrease - mg/dL
150 – 200
125 – 149
100 – 124
< 100 or 
associated with 
gross bleeding 
or disseminated 
intravascular
coagulation (DIC)
*
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** “ULN” is the upper limit of the normal range.
Urine *
Mild (Grade 1)
Moderate 
(Grade 2)
Severe (Grade 3) Potentially 
Life 
Threatening 
(Grade 4)
Protein
Trace
1+
2+
Hospitalization or
dialysis
Glucose
Trace
1+
2+
Hospitalization 
for
hyperglycemia
Blood 
(microscopic) –
red blood cells 
per
high power field (rbc/hpf)
1 - 10
11 – 50
> 50 and/or 
gross blood
Hospitalization 
or packed red 
blood cells 
(PRBC)
transfusion
*
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.


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IV. REFERENCES 
20. National Cancer Institute Common Toxicity Criteria, April 30, 1999. 
(http://ctep.cancer.gov/reporting/CTC-3.html) 
21. Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 1992. 
(http://rcc.tech-res-intl.com/tox_tables.htm) 
22. The Brighton Collaboration. Finalized Case Definitions and Guidelines. 
(http://brightoncollaboration.org/internet/en/index/definition  
guidelines.html) 
23. HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; September 
18, 2002. (http://rcc.tech-res-intl.com/tox_tables.htm) 
24. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
December 2004. 
(http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAIDSAEGra 
dingTable.pdf) 
25. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. New 
England Journal of Medicine. 2004;351:1548-1563.