Clinical trial NCT04251910
Conditions: Agitation,Psychomotor Dementia
Sponsor: BioXcel Therapeutics Inc
Start date: 2019-12-27; Completion date: 2022-01-24
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an adaptive Phase 1b/2 trial design. It is randomized, double-blind, placebo-controlled, multiple ascending dose study assessing efficacy, pharmacokinetics, safety and tolerability of BXCL-501 dosing in adult (65 years and older) males and females with acute agitation associated with dementia. Evaluation of 3 doses are planned.

Detailed description:
This is a Phase 1b/2 randomized, double-blind, placebo controlled, ascending dose finding study assessing efficacy, pharmacokinetics, safety, and tolerability of BXCL501 with 3 dosing groups in adult (65 years and older) males and females with acute agitation associated with all forms of dementia. Evaluation of three (3) doses of sublingual BXCL 501 are planned. Cohort 1, Cohort 2 and Cohort 3 will be given 30µg, 60µg and 90µg dose respectively of BXCL501 or placebo. Subjects assigned to Cohort 3 will participate in a 1-week safety observation before being enrolled.

This is an adaptive design as doses selected for testing may be different from these, based upon safety reviews. Doses lower or higher may be chosen to test, up to 180µg, and additional subjects may be added to a cohort. BXCL501 films may be divided in half if needed to deliver half-dose strengths. At least 30 subjects (10 per cohort) will be enrolled at up to 3 study sites in the United States. In Part B a total of 46 subjects will receive BXCL501 40 μg or matching placebo film.

The effects of BXCL 501 on acute agitation will be assessed by the following scales: Pittsburgh Agitation Scale (PAS), the PANSS-EC (PEC), Cohen-Mansfield Agitation Inventory (CMAI), CGI-Severity for Agitation and CGI Improvement for Agitation. Adverse Events (AEs), clinical laboratory tests, ECG, and vital signs will be monitored, and all observed.

Arms: arm 1: Cohort 1 consists of 10 patients out of whom 8 patients receive 30 Micrograms film and the remaining 2 patients receive a placebo arm 2: Cohort 2 consists of 10 patients out of whom 8 patients receive 60 Micrograms film and the remaining 2 patients receive a placebo.

Additional 20 subjects receive 60 Micrograms or placebo. arm 3: Cohort 3 consists of 10 patients out of whom 8 patients receive 90 Micrograms film and the remaining 2 patients receive a placebo arm 4: Part B cohort consists 46 subjects receiving 40 Micrograms or placebo
Interventions: intervention 1: Sublingual film containing Dexmedetomidine intervention 2: Sublingual Placebo Film
Intervention descriptions: intervention 1: Sublingual film containing Dexmedetomidine intervention 2: Sublingual placebo film that matches BXCL501

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
A PHASE Ib/II, MULTICENTER, RANDOMIZED, 
DOUBLE BLIND, PLACEBO CONTROLLED, 
ASCENDING DOSE FINDING, EFFICACY, 
PHARMACOKINETIC AND SAFETY STUDY OF 
BXCL501 IN AGITATION ASSOCIATED WITH 
DEMENTIA 
 
NCT04251910 
02/04/2021 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  1  of  7 4  
 
A  P H A S E I b /II, M U L TI C E N T E R,  R A N D O MI Z E D,  D O U B L E  B LI N D,  P L A C E B O 
C O N T R O L L E D,  A S C E N DI N G  D O S E  FI N DI N G,  E F FI C A C Y,  P H A R M A C O KI N E TI C  A N D 
S A F E T Y  S T U D Y  O F  B X C L 5 0 1 I N  A GI T A TI O N  A S S O CI A T E D  WI T H  D E M E N TI A  
 
 
 
P R O T O C O L  N U M B E R:   
B X C L 5 0 1 -1 0 3  
 
 
S T U D Y  P H A S E:  
P h as e I b/II  
 
 
I N D  N U M B E R: 
1 4 0 1 8 4  
 
P R O T O C O L  V E R SI O N:   
7  
 
O RI GI N A L  P R O T O C O L  D A T E:   
0 5  N o v  2 0 1 9  
 
A M E N D M E N T  1  D A T E:   
2 0  N o v  2 0 1 9  
 
A M E N D M E N T  2  D A T E:  
 
A M E N D M E N T  3  D A T E:  
 
A M E N D M E N T  4  D A T E:  
 
A M E N D M E N T  5  D A T E:  
 
A M E N D M E N T  6  D A T E:  
 
0 7  D e c  2 0 1 9  
 
1 5 J ul  2 0 2 0 
 
0 3  S e p  2 0 2 0 
 
2 2  O ct  2 0 2 0 
 
0 4  F e b  2 0 2 1 
S P O N S O R E D  B Y:  
Bi o X c el  T h er a p e uti cs, I n c.  
5 5 5  L o n g  W h arf  Dri v e 
1 2 t h  Fl o or 
N e w  H a v e n,  C T  0 6 5 1 1 
P h o n e:   
 
 
 
T his st u d y  will  b e  p erf or m e d i n  c o m pli a n c e  wit h  G o o d  Cli ni c al  Pr a cti c es  a n d  a p pli c a bl e r e g ul at or y r e q uir e m e nts, 
i n cl u di n g t h e  ar c hi vi n g  of  ess e nti al  d o c u m e nts.  I nf or m ati o n  c o nt ai n e d i n t his  pr ot o c ol is  c o nfi d e nti al i n  n at ur e,  a n d 
m a y  n ot  b e  us e d,  di v ul g e d,  p u blis h e d , or  ot h er wis e  dis cl os e d t o  ot h ers  e x c e pt t o t h e  e xt e nt  n e c ess ar y t o  o bt ai n 
a p pr o v al  of t h e I nstit uti o n al  R e vi e w  B o ar d  or I n d e p e n d e nt  Et hi cs  C o m mitt e e,  or  as r e q uir e d  b y l a w.   P ers o ns t o 
w h o m t his i nf or m ati o n is  dis cl os e d s h o ul d  b e i nf or m e d t h at t his i nf or m ati o n is  c o nfi d e nti al  a n d  m a y  n ot  b e f urt h er 
dis cl os e d  wit h o ut t h e  e x pr ess  p er missi o n  of  Bi o X c el  T h er a p e uti cs,  I n c.
P P D


Bi o X c el 
 
T h er a p e uti cs, 
 
I n c. 
  
  
  C o nfi d e nti al 
  
  
  
  B X C L 5 0 1- 1 0 3 
 
 
 
Pr ot o c ol  B X C L 5 0 1- 1 0 3  –  V ersi o n  7,  0 4  F e b  2 0 2 1      
   
   
   
   
P a g e  2  of  7 4 
P R O T O C O L  A P P R O V A L 
 
A  P H A S E I b/II,  M U L TI C E N T E R,  R A N D O MI Z E D,  D O U B L E  B LI N D,  P L A C E B O 
C O N T R O L L E D,  A S C E N DI N G  D O S E  FI N DI N G,  E F FI C A C Y,  P H A R M A C O KI N E TI C  A N D 
S A F E T Y  S T U D Y  O F  B X C L 5 0 1 I N  A GI T A TI O N  A S S O CI A T E D  WI T H  D E M E N TI A 
 
 
P R O T O C O L  N U M B E R: 
B X C L 5 0 1- 1 0 3 
 
 
P R O T O C O L  V E R SI O N:   
7 
 
O RI GI N A L  P R O T O C O L  D A T E:   
0 5  N o v  2 0 1 9 
 
A M E N D M E N T  1  D A T E: 
 
A M E N D M E N T  2  D A T E: 
 
A M E N D M E N T  3  D A T E: 
 
A M E N D M E N T  4  D A T E: 
 
A M E N D M E N T  5  D A T E: 
 
A M E N D M E N T  6  D A T E: 
 
2 0  N o v  2 0 1 9 
 
0 7  D e c  2 0 1 9 
 
1 5 J ul  2 0 2 0 
 
0 3  S e p  2 0 2 0 
 
2 2  O ct  2 0 2 0 
 
0 4  F e b  2 0 2 1 
S P O N S O R
  Bi o X c el
 
T h er a p e uti cs,
 
I n c.
 
5 5 5  L o n g  W h arf  Dri v e 
1 2 t h  Fl o or 
N e w  H a v e n,  C T  0 6 5 1 1 
U S A 
 
S T U D Y  P R O D U C T 
B X C L 5 0 1 
 
 
S p o ns o r  A p p r o v al: 
 
D at e:   _ _ _ _ _ _ _ _ _ _ _      
Si g n at ur e:   _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
       
,   
 
        M e di c al  M o nit or 
P P D
P P D
P P D


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3  of  7 4  
1.   
P R O C E D U R E S I N  C A S E  O F  E M E R G E N C Y  
T a bl e  1. 1:   
S p o ns o r/ C R O  C o nt a ct I nf o r m ati o n 
R ol e i n  St u d y  
N a m e  
A d d r ess  a n d   
T el e p h o n e  N u m b e r  
Cli ni c al  St u d y  L e a d er 
, 
 
C hi ef  E x e c uti v e  Offi c er  
C o g niti v e  R es e ar c h  C or p or ati o n ( C R C) 
2 0 0  C e ntr al  A v e,  S uit e  1 2 3 0 
S ai nt  P et ers b ur g,  F L  3 3 7 0 1  
T el e p h o n e:  
 
C ell:   
 
 
Cli ni c al  O p er ati o ns  L e a d er  
,   
 
Dir e ct or,  Cli ni c al  Pr oj e cts  
C R C  
2 0 0  C e ntr al  A v e,  S uit e  1 2 3 0 
S ai nt  P et ers b ur g,  F L  3 3 7 0 1  
T el e p h o n e:  
 
C ell:   
 
 
M e di c al  M o nit or/  
2 4  h o ur  E m er g e n c y  C o nt a ct 
,  
  
C R C  
2 0 0  C e ntr al  A v e,  S uit e  1 2 3 0 
S ai nt  P et ers b ur g,  F L  3 3 7 0 1 
C ell:  
 
 
S e c o n d ar y  C o nt a ct: 
,  
 
Bi o X c el  T h er a p e uti cs, I n c.  
5 5 5  L o n g  W h arf  Dri v e 
1 2t h  Fl o or 
N e w  H a v e n,  C T  0 6 5 1 1 
C ell:  
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4  of  7 4  
2.   
I N V E S TI G A T O R  A G R E E M E N T  
P R O T O C O L  TI T L E:   
A  P H A S E I b/II,  M U L TI C E N T E R,  R A N D O MI Z E D,  D O U B L E 
B LI N D,  P L A C E B O  C O N T R O L L E D,  A S C E N DI N G  D O S E 
FI N DI N G,  E F FI C A C Y,  P H A R M A C O KI N E TI C  A N D  S A F E T Y 
S T U D Y  O F  B X C L 5 0 1 I N  A GI T A TI O N  A S S O CI A T E D  WI T H 
D E M E N TI A  
 
P R O T O C O L  N U M B E R:      
B X C L 5 0 1- 1 0 3 
 
I  h a v e r e a d t h e  pr ot o c ol  a n d  a gr e e t h at it,  al o n g  wit h t h e r elat e d  Cli ni c al  Tri al  A gr e e m e nt, 
c o nt ai ns  all t h e  d et ails  n e c ess ar y t o  c arr y  o ut t h e st u d y.  I  will  c o n d u ct t his st u d y  a c c or di n g t o t h e 
pr ot o c ol  a n d  will  c o m pl et e t h e st u d y i n t h e ti m e  a gr e e d.   P ot e nti al  a d diti o ns  or  m o difi c ati o ns t o 
t h e st u d y  will  b e  b y  m utu al  writt e n  a gr e e m e nt  b et w e e n  Bi o X c el  T h er a p e uti cs, I n c.  a n d  m e  a n d 
will  b e  d o c u m e nt e d  a n d fil e d, if r e q uir e d,  wit h t h e I nstit uti o n al  R e vi e w  B o ar d  a n d t h e  U nit e d 
St at es  F o o d  a n d  Dr u g  A d mi nistr ati o n. 
I  will  pr o vi d e  c o pi es  of t h e  pr ot o c ol  a n d  ot h er  p erti n e nt i nf or m ati o n t o  all i n di vi d u als r es p o nsi bl e 
f or  assisti n g  m e i n t h e st u d y. 
Bi o X c el  T h er a p e uti cs, I n c.,  C o g niti v e  R es e ar c h  C or p or ati o n,  a n d t h eir  d esi g n e es  will  h a v e 
a c c ess t o s o ur c e  d o c u m e nt ati o n fr o m  w hi c h  c as e r e p orts  h a v e  b e e n  g e n er at e d.  
 
 
I n v esti g at or 
Si g n at ur e:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    
D at e:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
I n v esti g at or 
N a m e ( pri nt):    _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
















Bi o X c el  T h er a p e uti cs, I n c.    
   
   
   
  
C o nfi d e nti al    
   
   
   
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
   
   
   
   
   
  
P a g e  1 2  of  7 4  
T a bl e  3. 1:  
S c h e d ul e  of  E v e nts  
A cti vit y  
P r e -
S c r e e ni n g 8, 9 
S c r e e ni n g  
P r e -
D os e 1 
T r e at m e nt  E v al u ati o n  D a y  1  
D a y  2 
F oll o w -U p 
( + 1 d a y ) 
D a y  3  
D a y  7  
( + 2 
d a ys ) 
Ti m e  p oi nt  
P r e -
t r e at m e nt 
P r e -
t r e at m e nt 
-1  h r 
t o 
ti m e  0 
5 
mi n  
1 0 
mi n  
1 5 
mi n  
3 0 
mi n  
1 
h r  
2 
h r  
4 
h r  
6 
h r  
8 
h r  
2 4  h r  
 
E n d 
of 
St u d y  
(-9/ + 1 2  h r)  
I nf or m e d  c o ns e nt 
X  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
M e di c al  hist or y  
X   
X   
  
  
  
  
  
  
  
  
  
  
 
  
 
D e m o gr a p hi cs  
X   
X   
  
  
  
  
  
  
  
  
  
  
 
  
 
W ei g ht  
X  
  
  
  
  
  
  
  
  
  
  
  
X   
  
 
H ei g ht  
X  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
Mi ni -M e nt al  St at e  e x a m   
X 
  
  
  
  
  
  
  
  
  
  
  
X   
  
 
Cli ni c al  D e m e nti a  R ati n g 
S c or e  
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
 
P h ysi c al  e x a m  
X   
X   
  
  
  
  
  
  
  
  
  
  
X   
  
 
S af et y l a b or at or y 
ass ess m e nts 3 
X  
 
  
  
  
  
  
  
  
  
  
  
  
X   
X  
U D S 1 0 
X 
X 1 1 
  
  
  
  
  
  
  
  
  
  
 
  
 
U TI  a n d  pr e g n a n c y  
 
X   
  
  
  
  
  
  
  
  
  
  
 
  
 
J o h ns  H o p ki ns  F all  Ris k 
Ass ess m e nt ( C o h ort  3  o nl y)  
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
E C G  wit h r h yt h m stri p 7 
X  
 
X  
  
  
 
  
 
X  
  
  
 
X   
  
 
P uls e  o xi m etr y  
 
  
X  
  
  
  
X  
X  
X  
X  
X  
X  
X 
  
 
R esti n g  vit al si g ns 2 
X   
X   
X   
  
  
  
X   
X   
X   
X   
X   
X   
X   
  
 
Ort h ost ati c  vit al si g ns 2 
X   
X   
X   
  
  
  
X  
X  
X   
X  
 
X   
X   
  
 


Bi o X c el  T h er a p e uti cs, I n c.    
   
   
   
  
C o nfi d e nti al    
   
   
   
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
   
   
   
   
   
  
P a g e  1 3  of  7 4  
A cti vit y  
P r e -
S c r e e ni n g 8, 9 
S c r e e ni n g  
P r e -
D os e 1 
T r e at m e nt  E v al u ati o n  D a y  1  
D a y  2 
F oll o w -U p 
( + 1 d a y ) 
D a y  3  
D a y  7  
( + 2 
d a ys ) 
Ti m e  p oi nt  
P r e -
t r e at m e nt 
P r e -
t r e at m e nt 
-1  h r 
t o 
ti m e  0 
5 
mi n  
1 0 
mi n  
1 5 
mi n  
3 0 
mi n  
1 
h r  
2 
h r  
4 
h r  
6 
h r  
8 
h r  
2 4  h r  
 
E n d 
of 
St u d y  
(-9/ + 1 2  h r)  
I n cl usi o n/ E x cl usi o n  crit eri a  
X   
X   
X   
  
  
 
  
  
  
  
  
  
 
  
 
R a n d o mi z ati o n  
 
 
X   
  
  
 
  
  
  
  
  
  
 
  
 
C M AI  
 
X  
X   
  
  
 
  
 
X 
  
  
  
 
 
X 
St u d y  dr u g  a d mi nistr ati o n 6 
 
 
X   
  
  
 
  
  
  
  
  
  
 
  
 
P A S  
X   
X   
X   
  
  
  
X   
X   
X   
X  
 
X   
X   
X  
X 
P E C 1 2 
X  
  
X  
  
  
 
X   
X   
X   
X  
 
X   
X   
X  
X 
A C E S  
 
  
X  
  
  
  
  
X  
X  
X  
  
X  
 
  
 
C GI -S e v erit y  ( a git ati o n) 
 
  
X  
  
  
  
  
 
X  
  
  
 
X 
  
 
C GI -I m pr o v e m e nt ( c h a n g e 
i n  a git ati o n) 
 
  
  
  
  
  
X   
X   
X   
X  
 
X  
 
  
 
C- S S R S  
X   
X   
  
  
  
 
  
  
  
  
  
 
X   
  
 
B u c c al ( S L)  ass ess m e nt 5 
 
  
  
X  
X  
X   
X  
 
X   
X  
  
 
X   
  
 
P K s a m pli n g 4 
 
  
  
  
  
  
X  
X   
X *   
X  
 
X   
X   
  
 
C o n c o mit a nt  m e di c ati o ns   
X 
X   
X   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
X   
X  
A d v ers e  e v e nts  
X   
X   
X   
X   
X   
X  
X   
X   
X   
X   
X   
X   
X   
X   
X  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
   
   
  
C o nfi d e nti al    
   
   
   
   
   
  
B X C L 5 0 1 -1 0 3  
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
   
   
   
   
   
  
P a g e  1 4  of  7 4  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
   
   
  
C o nfi d e nti al    
   
   
   
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
   
   
   
   
   
  
P a g e  1 5  of  7 4  
T a bl e  3. 2:  
S c h e d ul e  of  E v e nts  –  1- w e e k  S af et y  O bs e r v ati o n ( C o h o rt  3  O nl y) 
A cti vit y  
D a y  O 1  
D a y  O 2  
D a y  O 3  
D a y  O 4  
D a y  O 5  
D a y  O 6  
D a y  O 7 
Ti m e  p oi nt  
A M  
P M 1 
A M  
P M 1 
A M  
P M 1 
A M  
P M 1 
A M  
P M 1 
A M  
P M 1 
A M  
P M 1 
R esti n g  vit al si g ns 2 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
Ort h ost ati c  vit al si g ns 2 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
R e c or di n g  of f alli n g  a n d 
s y n c o p e 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
C o n c o mit a nt  m e di c ati o ns   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
A d v ers e  e v e nts  
X   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  1 6  of  7 4  
4.   
T A B L E  O F  C O N T E N T S  
1.  
P R O C E D U R E S I N  C A S E  O F  E M E R G E N C Y  ................................................................. 3 
2.  
I N V E S TI G A T O R  A G R E E M E N T .................................................................................... 4 
3.  
S Y N O P SI S  ........................................................................................................................ 5 
4.  
T A B L E  O F  C O N T E N T S  ................................................................................................ 1 6 
4. 1.  
LI S T  O F  T A B L E S  .......................................................................................................... 2 0 
5.  
LI S T  O F  A B B R E VI A TI O N S  A N D  D E FI NI TI O N S  O F  T E R M S  ................................. 2 1 
6.  
I N T R O D U C TI O N ........................................................................................................... 2 4 
6. 1.  
B a c k gr o u n d  a n d  R ati o n al e .............................................................................................. 2 4  
6. 2.  
D es cri pti o n  of  B X C L 5 0 1 ................................................................................................ 2 5  
6. 3.  
N o n -Cli ni c al  P h ar m a c ol o g y  ............................................................................................ 2 5 
6. 3. 1.  
P h ar m a c o d y n a mi cs .......................................................................................................... 2 5  
6. 4.  
Cli ni c al  E x p eri e n c e  a n d  P h ar m a c o ki n eti cs  ..................................................................... 2 6 
6. 4. 1.  
Si n gl e  As c e n di n g  D os e  St u d y ( St u d y  B X C L 5 0 1- 1 0 1) ................................................... 2 6  
6. 4. 2.  
 ..................................................................................... 2 7 
6. 4. 3.  
 ............................................. 2 9 
7.  
O BJ E C TI V E S  .................................................................................................................. 3 1 
7. 1.  
Pri m ar y  E n d p oi nt ............................................................................................................. 3 1  
7. 2.  
S e c o n d ar y  E n d p oi nts ....................................................................................................... 3 1  
8.  
S T U D Y  D E SI G N  ............................................................................................................ 3 2 
8. 1.  
O v er all  St u d y  D esi g n  a n d  Pl a n ........................................................................................ 3 2  
8. 2.  
St o p pi n g  Crit eri o n ........................................................................................................... 3 5  
8. 3.  
St u d y  Sit es ....................................................................................................................... 3 6  
9.  
S U BJ E C T  P O P U L A TI O N  .............................................................................................. 3 7 
9. 1.  
S el e cti o n  of  St u d y  P o p ul ati o n ......................................................................................... 3 7  
9. 1. 1.  
I n cl usi o n  Crit eri a ............................................................................................................. 3 7 
9. 1. 2.  
E x cl usi o n  Crit eri a  ............................................................................................................ 3 7 
9. 2.  
R e m o v al  of  S u bj e cts fr o m  T h er a p y  or  Ass ess m e nt ........................................................ 3 9  
1 0.  
S T U D Y  T R E A T M E N T S  ................................................................................................ 4 0 
1 0. 1.  
M et h o d  of  Assi g ni n g  S u bj e cts t o  Tr e at m e nt  Gr o u ps ...................................................... 4 0  
1 0. 2.  
I d e ntifi c ati o n  of I n v esti g ati o n al  Pr o d u ct ......................................................................... 4 0 
C CI
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  1 7  of  7 4  
1 0. 3.  
Tr e at m e nt  A d mi nistr ati o n  ............................................................................................... 4 0 
1 0. 4.  
St or a g e ............................................................................................................................. 4 1  
1 0. 5.  
L a b eli n g  ........................................................................................................................... 4 1 
1 0. 6.  
Dr u g  A c c o u nt a bilit y  ........................................................................................................ 4 1 
1 0. 7.  
Bli n di n g  a n d  U n bli n di n g  Tr e at m e nt  Assi g n m e nt ............................................................ 4 1  
1 0. 8.  
S el e cti o n  of  D os e i n t h e  St u d y ........................................................................................ 4 2  
1 0. 9.  
Tr e at m e nt  C o m pli a n c e  .................................................................................................... 4 2 
1 0. 1 0.  
C o n c o mit a nt  M e di c ati o ns ................................................................................................ 4 2  
1 0. 1 0. 1.  P er mitt e d  T h er a pi es  ......................................................................................................... 4 3 
1 0. 1 0. 2.  Pr o hi bit e d  T h er a pi es ........................................................................................................ 4 3  
1 1.  
S T U D Y  P R O C E D U R E S  ................................................................................................. 4 4 
1 1. 1.  
Pr e -S cr e e ni n g  .................................................................................................................. 4 4 
1 1. 1. 1.  O n e -w e e k  S af et y  L e a d -i n ( C o h ort  3  O nl y) ..................................................................... 4 5 
1 1. 2.  
S cr e e ni n g  ......................................................................................................................... 4 5 
1 1. 3.  
Pr e -D os e  .......................................................................................................................... 4 5 
1 1. 4.  
D a y  1,  Tr e at m e nt  E v al u ati o n ........................................................................................... 4 6  
1 1. 5.  
D a y  2 ( + 1),  F oll o w- U p  .................................................................................................... 4 6 
1 1. 6.  
D a y  3  ............................................................................................................................... 4 7 
1 1. 7.  
D a y  7  +  2  D a ys ................................................................................................................ 4 7  
1 2.  
S T U D Y  A S S E S S M E N T S  ............................................................................................... 4 8 
1 2. 1.  
Effi c a c y  ............................................................................................................................ 4 8 
1 2. 1. 1.  P A N S S - E x cit e d  C o m p o n e nt ( P E C) ................................................................................ 4 8 
1 2. 1. 2.  C o h e n  M a nsfi el d  A git ati o n I n v e nt or y ( C M AI) ............................................................... 4 8  
1 2. 1. 3.  A git ati o n -C al m n ess  E v al u ati o n  S c al e ( A C E S)  ............................................................... 4 8 
1 2. 1. 4.  Pitts b ur g  A git ati o n  S c al e ( P A S)  ...................................................................................... 4 8 
1 2. 1. 5.  C GI - S  a n d  C GI-I ............................................................................................................. 4 8 
1 2. 2.  
Cli ni c al  Di a g n osis  a n d  D es cri pti o n  of  D e m e nti a  ............................................................ 4 9 
1 2. 2. 1.  M M S E  ............................................................................................................................. 4 9 
1 2. 2. 2.  C D R  S c or e  ....................................................................................................................... 5 0 
1 2. 3.  
P h ar m a c o ki n eti cs  ............................................................................................................. 5 0 
1 2. 3. 1.  S a m pl e  C oll e cti o n  &  Pr o c essi n g  ..................................................................................... 5 0 
1 2. 3. 2.  S a m pl e  St or a g e  ................................................................................................................ 5 1 
1 2. 3. 3.  S a m pl e  S hi p m e nt ............................................................................................................. 5 1  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  1 8  of  7 4  
1 2. 4.  
A n al yti c al  Pr o c e d ur es  ...................................................................................................... 5 1 
1 2. 4. 1.  Bi o a n al yti c al  S a m pl e  A n al ys es  ....................................................................................... 5 1 
1 2. 4. 2.  Bi o a n al yti c al  M et h o d ol o g y ............................................................................................. 5 2  
1 2. 5.  
S af et y  ............................................................................................................................... 5 2 
1 2. 5. 1.  A d v ers e  E v e nts  ................................................................................................................ 5 2 
1 2. 5. 1. 1.  A d v ers e  E v e nt  D efi niti o ns .............................................................................................. 5 2  
1 2. 5. 1. 2.  Eli citi n g  a n d  D o c u m e nti n g  A d v ers e  E v e nts .................................................................... 5 3  
1 2. 5. 1. 3.  R e p orti n g  A d v ers e  E v e nts ............................................................................................... 5 3  
1 2. 5. 1. 4.  F oll o w- u p  of  A d v ers e  E v e nts .......................................................................................... 5 6  
1 2. 5. 2.  J o h ns  H o p ki ns  F all  Ris k  Ass ess m e nt  T o ol ..................................................................... 5 6 
1 2. 5. 3.  C- S S R S  ............................................................................................................................ 5 6 
1 2. 5. 4.  L a b or at or y  S af et y  Ass ess m e nts ....................................................................................... 5 6  
1 2. 5. 5.  Vit al  Si g ns  ....................................................................................................................... 5 7 
1 2. 5. 6.  El e ctr o c ar di o gr a m ........................................................................................................... 5 7  
1 2. 5. 7.  P h ysi c al  E x a mi n ati o n  ...................................................................................................... 5 7 
1 2. 5. 8.  C o n c o mit a nt  M e di c ati o ns ................................................................................................ 5 7  
1 3.  
S T A TI S TI C A L  M E T H O D S  ........................................................................................... 5 8 
1 3. 1.  
G e n e r al  C o nsi d er ati o ns ................................................................................................... 5 8 
1 3. 2.  
A n al ysis  P o p ul ati o ns ....................................................................................................... 5 8  
1 3. 3.  
St atisti c al  A n al ys es  .......................................................................................................... 5 8 
1 3. 3. 1.  S u bj e ct  Dis p ositi o n  a n d  D e m o gr a p hi c  C h ar a ct eristi cs ................................................... 5 8  
1 3. 3. 2.  Effi c a c y  A n al ys es  ............................................................................................................ 5 8 
1 3. 3. 3.  S af et y  A n al ys es  ............................................................................................................... 5 9 
1 3. 3. 4.  P h ar m a c o ki n eti c  A n al ys es  ............................................................................................... 5 9 
1 3. 3. 5.  I nt eri m  A n al ys es .............................................................................................................. 5 9 
1 3. 4.  
S a m pl e  Si z e  D et er mi n ati o n  ............................................................................................. 6 0 
1 4.  
S T U D Y  C O N D U C T  ....................................................................................................... 6 1 
1 4. 1.  
S p o ns or  a n d I n v esti g at or  R es p o nsi biliti es ....................................................................... 6 1  
1 4. 1. 1.  S p o ns or  R es p o nsi biliti es ................................................................................................. 6 1  
1 4. 1. 2.  I n v esti g at or  R es p o nsi biliti es ........................................................................................... 6 1 
1 4. 2.  
Sit e I niti ati o n  ................................................................................................................... 6 1 
1 4. 3.  
St u d y  D o c u m e nts ............................................................................................................. 6 2  
1 4. 3. 1.  G o o d  Cli ni c al  Pr a cti c e  D o c u m e nts  ................................................................................. 6 2 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  1 9  of  7 4  
1 4. 3. 2.  C as e  R e p ort  F or ms  .......................................................................................................... 6 2 
1 4. 3. 3.  S o ur c e  D o c u m e nts ........................................................................................................... 6 3  
1 4. 4.  
D at a  Q u alit y  C o ntr ol ....................................................................................................... 6 3  
1 4. 4. 1.  M o nit ori n g  Pr o c e d ur es .................................................................................................... 6 3  
1 4. 4. 2.  D at a  M a n a g e m e nt  ............................................................................................................ 6 4 
1 4. 4. 3.  Q u alit y  Ass ur a n c e/ A u dit ................................................................................................. 6 4  
1 4. 5.  
St u d y  T er mi n ati o n ........................................................................................................... 6 4  
1 4. 5. 1.  R e g ul ar  St u d y  T er mi n ati o n ............................................................................................. 6 4  
1 4. 5. 2.  Pr e m at ur e  St u d y  T er mi n ati o n  .......................................................................................... 6 4 
1 4. 6.  
St u d y  Sit e  Cl os ur e ........................................................................................................... 6 5  
1 4. 6. 1.  R e c or d  R et e nti o n  ............................................................................................................. 6 5 
1 4. 6. 2.  S a m pl e  R et e nti o n  ............................................................................................................. 6 6 
1 4. 7.  
C h a n g es t o t h e  Pr ot o c ol ................................................................................................... 6 6  
1 4. 8.  
Us e  of I nf or m ati o n  .......................................................................................................... 6 6 
1 5.  
FI N A L  C LI NI C A L  S T U D Y  R E P O R T  ........................................................................... 6 7 
1 6.  
E T HI C A L  A N D  L E G A L  C O N SI D E R A TI O N S  ............................................................. 6 8 
1 6. 1.  
D e cl ar ati o n  of  H elsi n ki  a n d  G o o d  Cli ni c al  Pr a cti c e  ....................................................... 6 8 
1 6. 2.  
S u bj e ct I nf or m ati o n  a n d I nf or m e d  C o ns e nt .................................................................... 6 8  
1 6. 3.  
A p pr o v al  b y I nstit uti o n al  R e vi e w  B o ar d ......................................................................... 6 8  
1 7.  
R E F E R E N C E S  ................................................................................................................ 6 9 
A P P E N DI X  A  ................................................................................................................................ 7 0 
 
 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 0  of  7 4  
4. 1.   
LI S T  O F  T A B L E S  
T a bl e   1. 1: S p o ns or/ C R O  C o nt a ct I nf or m ati o n  .............................................................................. 3 
T a bl e   3. 1: S c h e d ul e  of  E v e nts ..................................................................................................... 1 2  
T a bl e  3. 2:  S c h e d ul e  of  E v e nts  –  1- w e e k  S af et y  O bs er v ati o n ( C o h ort  3  O nl y) ........................... 1 5  
T a bl e   6. 1: Pr eli mi n ar y  St u d y  O ut p ut fr o m  St u d y  B X C L 5 0 1- 1 0 2 ............................................... 2 9  
 
 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 1  of  7 4  
5.   
LI S T  O F  A B B R E VI A TI O N S  A N D  D E FI NI TI O N S  O F  T E R M S  
A b b r e vi ati o n  
D efi niti o n  
A C E S  
A git ati o n -C al m n ess  E v al u ati o n  S c al e  
A E  
A d v ers e  e v e nt  
A N C O V A  
A n al ysis  of  c o v ari a n c e  
A PI  
A cti v e  P h ar m a c e uti c al I n gr e di e nt  
A U C  
Ar e a  u n d er t h e  pl as m a  c o n c e ntr ati o n  vs ti m e  c ur v e  
B P  
Bl o o d  pr ess ur e  
B MI  
B o d y  m ass  in d e x  
C 
C elsi us/ C e nti gr a d e  
C D R  
Cli ni c al  D e m e nti a  R ati n g  S c al e  
C GI -I 
Cli ni c al  Gl o b al I m pr essi o n -I m pr o v e me nt  
C GI - S 
Cli ni c al  Gl o b al I m pr essi o n -S e v erit y  
C LI A  
Cli ni c al  L a b or at or y I m pr o v e m e nt  A m e n d m e nts  
C M AI  
C o h e n -M a nsfi el d  A git ati o n I n v e nt or y  
C m a x  
M a xi m u m  pl as m a  c o n c e ntr ati o n  
C N S  
C e ntr al  n er v o us s yst e m  
C R F  
C as e  re p ort  for m  
C R O  
C o ntr a ct  res e ar c h  o r g a ni z ati o n 
C S R  
Cli ni c al  st u d y re p ort  
C- S S R S  
C ol u m bi a -S ui ci d e  S e v erit y  R ati n g  S c al e  
C T C A E  
C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts  
D B P  
Di ast oli c  bl o o d  pr ess ur e  
D L T  
D os e  li miti n g to xi cit y  
D S M  
Di a g n osti c  a n d  St atisti c al  M a n u al  of  M e nt al  Dis or d ers  
E C G  
El e ctr o c ar di o gr a m  
E D T A  
Et h yl e n e di a mi n et etr a a c eti c  a ci d  
E T  
E arl y  ter mi n ati o n  
F D A  
F o o d  a n d  Dr u g  A d mi nistr ati o n  
F D & C  
F o o d,  Dr u g,  a n d  C os m eti c  A ct  
g 
G r a m 
G A B A  
G a m m a - ami n o  b ut yri c  a ci d  
G C P  
G o o d  Cli ni c al  Pr a cti c es  
H Cl  
H y dr o c hl ori d e  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 2  of  7 4  
A b b r e vi ati o n  
D efi niti o n  
H R  
H e art r at e  
hr  
H o ur  
I C H 
I nt er n ati o n al C o u n cil f or  H ar m o nis ati o n  
I C U 
I nt e nsi v e c ar e  u nit  
I M 
I ntr a m us c ul ar 
I R B 
I nstit uti o n al  R e vi e w  B o ar d 
I T T 
I nt e nt to  Tr e at  
I U D 
I ntr a ut eri n e d e vi c e  
I V  
I ntr a v e n o us 
k g  
K il o gr a m 
L A R  
L e g all y  a ut h ori z e d r e pr es e nt ati v e  
L C/ M S/ M S  
Li q ui d  c hr o m at o gr a p h y -t a n d e m  m ass s p e ctr o m etr y 
L D  
List e d  d r u g 
L O C F  
L ast  o bs er v ati o n  c arri e d  for w ar d  
M e d D R A  
M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  
m g  
M illi gr a m 
M H R A  
M e di ci n es  a n d  H e alt h c ar e  pr o d u cts  R e g ul at or y  A g e n c y  
Mi n  
Mi n ut es  
m L  
M illilit er 
m m  
M illi m et er 
m m H G  
M illi m et ers  of  m er c ur y 
M M R M  
Mi x e d  m o d el r e p e at e d  m e as ur es  
M M S E  
Mi ni  M e nt al  St at us  E x a m  
M S  
M ass s p e ctr o m etr y  
M T D  
M a xi m u m t ol er at e d  d os e  
M W  
M ol e c ul ar  w ei g ht  
P A N S S -E C/ P E C   
P ositi v e  a n d  N e g ati v e  S y n dr o m e  S c al e/  P ositi v e  a n d  N e g ati v e  S y n dr o m e  S c al e  – 
E x cit e d  C o m p o n e nt  
P A S  
Pitts b ur g h  A git ati o n  S c al e  
P D  
P h ar m a c o d y n a mi cs  
p g  
P i c o gr a m 
p H  
M e as ur e  of  h y dr o g e n i o n  c o n c e ntr ati o n  
PI  
Pri n ci p al I n v esti g at or  
P K  
P h ar m a c o ki n eti c  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 3  of  7 4  
A b b r e vi ati o n  
D efi niti o n  
p o  
O r al/B y  m o ut h  
P O C  
Pr o of  of  C o n c e pt  
P P  
P er  Pr ot o c ol  
R A S S  
R a ms a y  S e d ati o n  S c al e  
S A E  
S eri o us  a d v ers e  e v e nt  
S A P  
St atisti c al  a n al ysis  p l a n 
S B P  
S yst oli c  bl o o d  pr ess ur e  
S L  
S u bli n g u al   
T H C  
T etr a h y dr o c a n n a bi n ol  
T m a x  
Ti m e t h at  dr u g is  pr es e nt  at t h e  m a xi m u m  c o n c e ntr ati o n i n s er u m  
µ g/ µ c g  
Mi cr o gr a m  
U D S  
Uri n e  d r u g scr e e n  
U S  
U nit e d  St at es  
U S P  
U nit e d  St at es  P h ar m a c o p ei a   
 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 4  of  7 4  
6.   
I N T R O D U C TI O N 
6. 1.   
B a c k g r o u n d  a n d  R ati o n al e  
B a c k gr o u n d 
A git ati o n is  a s e v er e,  disr u pti v e,  a n d  m or bi d  c o m pli c ati o n  of  m a n y  c hr o ni c  m e nt al ill n ess es, 
i n cl u di n g s c hi z o p hr e ni a ( Oss er  a n d  Si g a d el,  2 0 0 1),  d e m e nti a ( C o n n  a n d  Li eff,  2 0 0 1),  a n d  bi p ol ar 
dis or d er ( Al d erf er  a n d  All e n,  2 0 0 3).   C urr e ntl y, t h e st a n d ar d  of  c ar e i n t h e tr e at m e nt  of  a c ut e 
a git ati o n i n t h e  d e m e nt e d  el d erl y  p o p ul ati o n is  a nti- ps y c h oti cs  a n d  or  b e n z o di a z e pi n es.   T h o u g h 
effi c a c y  h as  b e e n  d e m o nstr at e d f or  e a c h  of t h es e  a g e nts,  ol d er  p e o pl e  ar e  m or e s e nsiti v e t o t h e 
si d e  eff e cts  pr o d u c e d  b y t h es e  dr u gs  a n d i n f a ct t h er e  ar e iss u es  wit h  m ort alit y  ass o ci at e d  wit h 
t h e  us e  of  a nti- ps y c h oti c  dr u gs i n t his  p o p ul ati o n ( S al z m a n  et  al.,  2 0 0 8).  I n  a d diti o n,  o ns et  of 
a cti o n  aft er  b ot h  or al  a n d i ntr a m us c ul ar  a d mi nistr ati o n  of s o m e  of t h es e  a g e nts is t y pi c all y 
3 0- 6 0  mi n  d u e t o sl o w  a bs or pti o n i nt o t h e s yst e mi c  cir c ul ati o n.   Sl o w  o ns et  of  a cti o n  c a n  e xt e n d 
t h e s uff eri n g  of  a git at e d  p ati e nts  a n d i n cr e as es t h e  n e e d f or  p h ysi c al r estr ai nt  or s e cl usi o n ( All e n 
et  al.,  2 0 0 3).   A c c or di n g t o  e x p ert  c o ns e ns us  g ui d eli n es  d e v el o p e d  b y  5 0 l e a di n g  U S  e x p erts i n 
b e h a vi or al  e m er g e n ci es ( All e n  et  al.,  2 0 0 1), s p e e d  of  o ns et  of  a nti- a git ati o n  eff e cts  w as  vi e w e d 
as  o n e  of t h e  m ost i m p ort a nt f a ct ors i n s el e cti n g  a n  a git ati o n tr e at m e nt.   A n  alt er n ati v e 
n o n-i n v asi v e,  p ot e nti all y s af er  m e di c ati o n  w hi c h  pr o d u c es  a r a pi d  c al mi n g  eff e ct  t h at  all o ws 
p ati e nts t o  p arti ci p at e i n t h eir  c ar e  a n d tr e at m e nt  w o ul d fi n d  us e i n t h e  p h ar m a c ol o gi c al 
m a n a g e m e nt  of  a c ut e  a git ati o n.  
Bi o X c el  T h er a p e uti cs , I n c. is  d e v el o pi n g  a s u bli n g u al fil m f or m ul ati o n  of  d e x m e d et o mi di n e 
( B X C L 5 0 1) f or t h e  a c ut e tr e at m e nt  of  h y p er- ar o us al i n  a git at e d  p ati e nts  wit h s c hi z o p hr e ni a, 
bi p ol ar  dis or d er,  a n d  d e m e nti a.   D e x m e d et o mi di n e is  a  hi g hl y s el e cti v e  α 2  a dr e n o c e pt or  a g o nist 
o n  pr es y n a pti c  n e ur o ns.   T h e sti m ul ati o n  of t h es e r e c e pt ors i n t h e l o c us  c o er ul e us l e a ds t o  a 
d e cr e as e  i n  n or e pi n e p hri n e r el e as e fr o m  pr es y n a pti c  n e ur o ns  wit h i n hi biti o n  of  p osts y n a pti c 
a cti v ati o n,  w hi c h  att e n u at es  c e ntr al  n er v o us s yst e m ( C N S)  ar o us al,  a n d  di mi nis h es t h e fi g ht- or-
fli g ht r es p o ns e ( M H R A,  2 0 1 4).  
 
 
  I n  a d diti o n,  b e c a us e it 
e nt ers t h e  bl o o d str e a m  dir e ctl y  b y t h e s u bli n g u al r o ut e  a n d  b y p ass es first- p ass  m et a b olis m i n 
li v er,  d e x m e d et o mi di n e fr o m  B X C L 5 0 1 is l ess s us c e pti bl e t o  v ari ati o ns i n  h e p ati c f u n cti o n t h a n 
or all y  a d mi nist er e d  dr u gs. 
D e x m e d et o mi di n e is  c urr e ntl y  a p pr o v e d i n t h e  U nit e d  St at es ( U S)  as t h e i ntr a v e n o us i nj e ct a bl e 
f or m ul ati o n,  Pr e c e d e x®  ( Pr e c e d e x  U S  P a c k a g e I ns ert,  2 0 1 6), f or  a c ut e  pr o c e d ur al  a n d I C U 
s e d ati o n. 
D e x m e d et o mi di n e  h as  b e e n  a d mi nist er e d  b y t h e  or al,  n as al,  a n d  or al  m u c os al r o ut es i n  b ot h 
n o n cli ni c al  a n d  cli ni c al st u di es  as r e p ort e d i n t h e  p u blis h e d  lit er at ur e,  wit h  n o r o ut e-s p e cifi c 
s af et y si g n als ( or al  m u c os al  or  g astr oi nt esti n al) i d e ntifi e d.  I n  h e alt h y  v ol u nt e ers  a n d  p ati e nts 
wit h  a git ati o n  ass o ci at e d  wit h s c hi z o p hr e ni a ( St u di es  B X C L 5 0 1- 1 0 1  a n d  B X C L 5 0 1- 1 0 2, 
r es p e cti v el y) si n gl e  d os es  of  1 0 µ g  t o  1 8 0  µ g  B X C L 5 0 1  pr o d u c e d s yst e mi c  d e x m e d et o mi di n e 
e x p os ur es ( C m a x   a n d  A U Cs) s u bst a nti all y l o w er t h a n  Pr e c e d e x  us e f or  pr o c e d ur al  a n est h esi a  wit h 
n o l o c al t ol er a bilit y iss u es.  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 5  of  7 4  
T his st u d y  will t est  a r a n g e  of  d os es  w hi c h  ar e  pr oj e ct e d t o  e x p os e s u bj e cts t o  pl as m a l e v els  of 
d e x m e d et o mi di n e t h at  w er e  ass o ci at e d  wit h  a s af e  a n d  eff e cti v e  a nti -a git ati o n  eff e ct  as  m e as ur e d 
b y  a r e d u cti o n i n  P E C s c or es  usi n g t h e r ef er e n c e I V  pr o d u ct.   Fr o m t h e r ef er e n c e  pr o d u ct,  w e 
k n o w t h e  m ost si g nifi c a nt  A Es  ar e  br a d y c ar di a/ h y p ot e nsi o n  a n d  u n ar o us a bl e s e d ati o n st e m mi n g 
fr o m  a  m or e r a pi d  d eli v er y  of  gr e at er  d os es  a n d  hi g h er  e x p os ur es  w hi c h  pr o d u c e  a n est h esi a.   T h e 
r a n g e  of  d os es s el e ct e d s h o ul d r e m ai n  w ell  b el o w  e x p os ur e  ass o ci at e d  wit h I V i n d u cti o n  of 
a n est h esi a,  alt h o u g h s o m n ol e n c e  m a y  b e  o bs er v e d  wit h  hi g h er  d os es  of  B X C L 5 0 1.  I n  a d diti o n, 
t h e st o p pi n g  crit eri o n  ar e f o c us e d  o n  c ar di o v as c ul ar  A Es  a n d  e x c essi v e s e d ati o n.   A git at e d 
s u bj e cts  ar e fr e q u e ntl y  d e h y dr at e d  a n d  e x h a ust e d fr o m  ps y c h o m ot or  a cti vit y.   T h us,  w hil e 
el e v at e d  vit a l si g ns t y pi c all y  a c c o m p a n y  a git ati o n,  as  a  c al mi n g  eff e ct is  a c hi e v e d, if 
u n a c c o m p a ni e d  b y r e h y dr ati o n  a n d r est, t h er e  m a y  b e  a  gr e at er  pr o p e nsit y f or s e nsiti v e s u bj e cts 
t o  e x p eri e n c e  c ar di o v as c ul ar  A Es  or  a p p e ar  e x c essi v el y s o m n ol e nt  es p e ci all y i n t his  p o p ul ati o n.  
Wit h r es p e ct t o s e d ati o n, r e c o v er y fr o m  pr ol o n g e d  e x c essi v e  ps y c h o m ot or  a cti vit y  n at ur all y 
i n cl u d es r estf ul n ess  a n d  e v e nt u al sl e e p.   Diff er e nti ati n g  n at ur al sl e e p  b e c a us e  of s u c c essf ul 
c al mi n g tr e at m e nt  as  o p p os e d t o t h at  ass o ci at e d  wit h  dr u g  e x p os ur e is t h er ef or e  pr o bl e m ati c.  
P arti c ul arl y  wit h  hi g h er  d os es  w e  e x p e ct t o  e n c o u nt er  mil d t o  m o d er at e s o m n ol e n c e, sl e e pi n ess 
or  dr o wsi n ess  a n d  will  m o nit or f or  e x c essi v e s e d ati o n  usi n g t h e  A C E S  ass ess m e nt.   T h e  a bilit y 
t o  ar o us e  a s u bj e ct  diff er e nti at es  A C E S s c or e  of  8 ( d e e p sl e e p) fr o m  9  ( u n ar o us a bl e sl e e p),  a 
l e v el  w hi c h  w e  will  ass u m e is  a n  u n a c c e pt a bl e  eff e ct r e pr es e nti n g  e x c essi v e s e d ati o n. 
T his st u d y is  d esi g n e d t o  a c c o m plis h  a d a pti v e r a pi d  d os e-r a n gi n g  b as e d  o n  P O C  d at a  o n  cli ni c al 
eff e cti v e n ess  a n d  w h at is  k n o w n  of  e xt e nsi v e s af et y  a n d t ol er a bilit y  of  hi g h er  d os es  d eli v er e d 
r a pi dl y  vi a I V.   A sit e-b as e d  es c al ati o n s c h e m a  wit h f o c us e d  p eri o di c s af et y r e vi e w  all o ws 
t esti n g  m ulti pl e  d os e  c o h orts  wit h t h e l o w est  d os es t est e d first,  a n d  hi g h er  d os es l ast.   Alt h o u g h 
e a c h i n di vi d u al sit e  a c cr u es  e x p eri e n c e  wit h  a s m all  n u m b er  of s eri all y  assi g n e d  es c al ati n g  d os es, 
at  a n  o v er all st u d y l e v el,  hi g h er  d os e  p a n els  a c cr u e sl o wl y  e n o u g h t o i d e ntif y  e arl y 
s af et y/t ol er a bilit y si g n als i n s m all  n u m b er s l o n g  b ef or e  hi g h  d os e  p a n els  c o m pl et e  e nr oll m e nt.  
A n  a d diti o n al  el e m e nt  all o ws i n v esti g at ors t o r e p e at  a  d os e f or l a c k  of  effi c a c y,  w hi c h  pr o vi d es 
ri c h  d at a  o n  pr o p orti o n  of r es p o n d ers/ n o n-r es p o n d ers  w hil e  eff e cti v el y  a u g m e nti n g t esti n g s af et y 
of  e x p os u r e t o t h e  n e xt  gr e at er  d os e l e v el. 
6. 2.   
D es c ri pti o n  of  B X C L 5 0 1  
 
 
 
N o s p e ci al tr a ns p ort  or st or a g e  c o n diti o ns  ar e r e q uir e d f or  B X C L 5 0 1.   P a c k a g e d fil ms  c a n  b e 
st or e d  at r o o m t e m p er at ur e ( 2 5 ° C)  a n d  a m bi e nt  h u mi dit y. 
6. 3.   
N o n -Cli ni c al  P h a r m a c ol o g y  
6. 3. 1.   
P h a r m a c o d y n a mi cs  
M e d et o mi di n e is  a r a c e mi c  mi xt ur e  of  2 st er e ois o m ers:   d e x m e d et o mi di n e  a n d 
l e v o m e d et o mi di n e.   T h e  a cti v e is o m er is  d e x m e d et o mi di n e,  w h er e as t h e  ot h er is o m er, 
l e v o m e d et o mi di n e, is  n o n-a cti v e.   D e x m e d et o mi di n e is  a  hi g hl y s el e cti v e  α 2  a dr e n o c e pt or 
a g o nist  o n  pr es y n a pti c  n e ur o ns.   T h e sti m ul ati o n  of t h es e r e c e pt ors l e a ds t o  a  d e cr e as e i n 
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 6  of  7 4  
n or e pi n e p hri n e r el e as e fr o m  pr es y n a pti c  n e ur o ns  wit h i n hi biti o n  of  p osts y n a pti c  a cti v ati o n, 
w hi c h  att e n u at es  C N S  ar o us al,  es p e ci all y i n t h e l o c us  c o er ul e us  of t h e  br ai n ( M H R A,  2 0 1 4). 
Si n c e t h e  p h ar m a c ol o gi c  eff e cts  of I V  d e x m e d et o mi di n e  h a v e  b e e n  c h ar a ct eri z e d,  Bi o X c el 
s o u g ht t o  e v al u at e  v ari o us  d e x m e d et o mi di n e  m etri cs f oll o wi n g  a d mi nistr ati o n  b y t h e s u bli n g u al 
( S L) r o ut e.   Bi o X c el  T h er a p e uti cs, I n c.  c o n d u ct e d  3  n o n cli ni c al st u di es t o  e v al u at e t h e 
p h ar m a c o d y n a mi cs  of  diff er e nt  B X C L 5 0 1 f or m ul ati o ns  as  c o m p ar e d t o  d e x m e d et o mi di n e 
a d mi nist er e d  b y  diff er e nt r o ut es, i n cl u di n g s u bli n g u al li q ui d  a d mi nistr ati o n. 
O v er all, t h e st u di es  d e m o nstr at e d t h at s u bli n g u al  a d mi nistr ati o n i n  a ni m al  m o d els  pr o d u c e 
s uffi ci e nt  e x p os ur e t o  eli cit  a  c al mi n g  eff e ct i n  a r at  m o d el  of  a g gr essi v e  b e h a vi or (i ntr u d er 
m o d el). 
6. 4.   
Cli ni c al  E x p e ri e n c e  a n d  P h a r m a c o ki n eti cs  
6. 4. 1.   
Si n gl e  As c e n di n g  D os e  St u d y ( St u d y  B X C L 5 0 1 - 1 0 1) 
T his st u d y  w as  a si n gl e sit e, r a n d o mi z e d,  d o u bl e- bli n d,  pl a c e b o  c o ntr oll e d,  P K, s af et y,  a n d 
t ol er a bilit y st u d y  wit h  4  d osi n g,  gr o u ps.   H e alt h y  a d ults  1 8 – 6 5  y e ars  of  a g e,  b ot h  m al es  a n d 
f e m al es,  w er e i n cl u d e d i n t his st u d y. 
T h e  pri m ar y  o bj e cti v e  of t his st u d y  w as t o  d et er mi n e t h e  P K, s af et y,  a n d t ol er a bilit y  of t h e 
v ari o us fil m str e n gt hs  of  B X C L 5 0 1 f or i d e ntifi c ati o n  of  a p pr o pri at e fil m  d os a g e str e n gt hs t o  b e 
c arri e d f or w ar d i nt o s u bs e q u e nt  cli ni c al tri als. 
T h e st u d y  e v al u at e d  3  d os es  of  B X C L 5 0 1 fil m i n  4  c o h orts  of  h e alt h y  a d ult  m al e  a n d f e m al e 
p arti ci p a nts.  I n  C o h orts  1  a n d  2 ( 1 0  µ g  a n d  2 0  µ g),  1 2  n e w  p arti ci p a nts  w er e  e nr oll e d  p er 
c o h ort, r a n d o mi z e d i n  a r ati o  of  2: 1,  wit h  8  p ati e nts r e c ei vi n g  B X C L 5 0 1 fil m  a n d  4  p ati e nts 
r e c ei vi n g  pl a c e b o fil m.   C o h ort  3  a n d  4 ( 4 0  µ g) i n cl u d e d  p arti cip a nts r e c ei vi n g  a cti v e tr e at m e nt 
w h o  h a d  c o m pl et e d tr e at m e nt i n  C o h orts  1  or  2,  as  w ell  as  n e w  p arti ci p a nts.   Si n gl e  d os es  u p t o 
4 0  µ g  B X C L 5 0 1  w er e  w ell -t ol er at e d.   F oll o wi n g  a  bli n d e d s af et y r e vi e w  of  C o h ort  3, t h e st u d y 
a c cr u e d  a d diti o n al s u bj e cts  at  4 0   µ g  a n d  di d  n ot  es c al at e t o  6 0  µ g,  p er  pr ot o c ol i n  C o h ort  4.   
 
 
 
 
T h e  P K   p o p ul ati o n  e v al u at e d  3  d os e l e v els:   1 0,  2 0,  a n d  4 0  µ g.   T h e  1 0 µ g   a n d  2 0 µ g  d os e l e v els 
c o nsist e d  of  8 s u bj e cts,  w hil e  4 0  µ g   d os e l e v el  c o nsist e d  of  12 s u bj e cts tr e at e d  wit h 
d e x m e d et o mi di n e.   E a c h  d os e l e v el  c o nsist e d  of  a cti v e  a n d  pl a c e b o s u bj e cts i n  a  2: 1 r ati o. 
 
   
 
 
  
   
 
 
 
 
   
 
 
 
   
 
   
 
   
 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 7  of  7 4  
i
 
   
 
 
   
   
 
 
 
   
 
 
   
   
 
   
 
   
 
 
 
6. 4. 2.  
 
C CI
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 8  of  7 4  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  2 9  of  7 4  
T a bl e  6. 1:  
P r eli mi n a r y  St u d y  O ut p ut f r o m  St u d y  B X C L 5 0 1 - 1 0 2 
D os e  
( u g) 
N  
C m a x  
( n g/ L) 
A U C l ast 
( n g• h/ L) 
A U C i nf 
( n g• h/ L / L)  
T m a x  
( h r) 
T ½  
( h r) 
2 0   
1 0   
3 7 ( 4 4 %)   
1 6 0 ( 4 5 %)   
2 3 9 ( 2 8 %)   
1. 7 ( 1  -4)   
3. 2 ( 3 1 %)  
6 0   
1 8   
1 3 3 ( 3 4 %)   
5 7 7 ( 6 0 %)   
6 7 5 ( 6 1 %)   
1. 5 ( 1  –  4)   
2. 6 ( 4 0 %)  
8 0   
1 8   
1 5 5 ( 4 2 %)   
8 1 7 ( 6 0 %)   
9 8 3 ( 5 5 %)   
1. 6 ( 1. 2  –  4. 3)   
3. 2 ( 3 6 %)  
1 2 0   
1 8   
2 2 1 ( 4 3 %)   
1 1 7 0 ( 7 9 %)   
1 3 7 8 ( 7 2 %)   
2. 0 ( 1  –  4)   
3. 3 ( 4 3 %)  
1 8 0   
1 8   
3 7 9 ( 6 8 %)   
2 2 9 4 ( 8 8 %)   
2 7 6 0 ( 9 1 %)   
2. 0 ( 1  –  8)   
3. 2 ( 5 3 %)  
C CI
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 0  of  7 4  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 1  of  7 4  
7.   
O B J E C TI V E S 
7. 1.   
P ri m a r y  E n d p oi nt  
T h e  pri m ar y  o bj e cti v e  of t his tri al is t o:  
D es cri b e t h e s af et y  a n d t ol er a bilit y  of si n gl e  d os es  of  B X C L 5 0 1 f or st u d y  of  effi c a c y i n 
tr e at m e nt  of  a c ut e  a git ati o n  ass o ci at e d  wit h  d e m e nti a. 
7. 2.   
S e c o n d a r y  E n d p oi nts  
T h e s e c o n d ar y  o bj e cti v es  of t his tri al  ar e t o  d et er mi n e:  
1.   D es cri b e t h e  o ns et  a n d  m a g nit u d e  of  c al mi n g  eff e cts  of  diff er e nt  d os es  of  B X C L 5 0 1  o n 
s y m pt o ms  of  a c ut e  a git ati o n  ass o ci at e d  wit h  d e m e nti a  as  m e as ur e d  b y t h e  Pitts b ur g h 
A git ati o n  S c al e ( P A S)  a n d  P A N S S - E C ( P E C)  as  c o m p ar e d t o  pl a c e b o. 
2.   D es cri b e t h e  d ur ati o n  of  c al mi n g  as  m e as ur e d  b y  P E C  a n d  A C E S. 
3.   D es cri b e t h e t ol er a bilit y  a n d s af et y  pr ofil e  of  B X C L 5 0 1,  as  d et er mi n e d  b y  a d v ers e  e v e nts 
a n d  vit al si g ns  vs.  pl a c e b o.  
4.   D es cri b e  cli ni c al  eff e cts  as  m e as ur e d  b y  Cli ni ci a n  Gl o b al I m pr essi o n  of  S e v erit y ( C GI- S) 
s c al e f or  a git ati o n  a n d t h e n i m pr o v e m e nt ( C GI- I)  aft er  dr u g  a d mi nistr ati o n. 
5.   D es cri b e t h e fr e q u e n c y  of  a git at e d  b e h a vi ors  usi n g t h e  C M AI  at  b as eli n er  a n d  2  h o urs 
p ost- d os e. 
6.   D et er mi n e t h e  a p p r o xi m at e  diss ol uti o n ti m e  of  B X C L 5 0 1 fil ms i n t h e s u bli n g u al s p a c e. 
7.   Ass ess t h e l o c al t ol er a bilit y  vi a  b u c c al  e x a mi n ati o n  aft er  d osi n g  B X C L 5 0 1 fil m.  
8.   D es cri b e t h e  P K   a n d  e x p os ur e  of  d e x m e d et o mi di n e  as  d eli v er e d  b y s u bli n g u al  B X C L 5 0 1 
d osi n g. 
9.   P art  B:   D es cri b e t h e  d ur ati o n  of  c al mi n g  as  m e as ur e d  b y t h e  3 s u p pl e m e nt ar y it e ms  of 
t h e  P A NS S.  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 2  of  7 4  
8.   
S T U D Y  D E SI G N  
8. 1.   
O v e r all  St u d y  D esi g n  a n d  Pl a n  
T his is  a n  a d a pti v e  P h as e I b/II tri al  d esi g n.  It is  a r a n d o mi z e d,  d o u bl e- bli n d,  pl a c e b o- c o ntr oll e d, 
m ulti pl e  as c e n di n g  d os e st u d y  ass essi n g  effi c a c y,  P K , s af et y,  a n d t ol er a bilit y  of  B X C L 5 0 1 
d osi n g i n  a d ult ( 6 5  y e ars  a n d  ol d er)  m al es  a n d f e m al es  wit h  a c ut e  a git ati o n  ass o ci at e d  wit h 
d e m e nti a.  
T h e st u d y  will  att e m pt t o  c h ar a ct eri z e  a s af e  a n d t ol er a bl e  d os e r a n g e t h at r es ults i n  a  c al mi n g 
eff e ct  as  m e as ur e d  usi n g t h e  Pitts b ur g h  A git ati o n  S c al e ( P A S)  b y  e v al u ati n g  at l e ast  1 0 s u bj e cts 
( 4: 1 r a n d o mi z ati o n t o  B X C L 5 0 1: pl a c e b o)  at  e a c h  of t h e  3  d os e l e v els.  It is  p ossi bl e t h at t h e 
s p o ns or  will  o pt t o  e x p a n d t h e  n u m b er  of sit es  a n d s u bj e cts  p er  d os e  ar m  as t h e st u d y  pr o gr ess es.  
T his  a d a pti v e  d esi g n is  b e n efi ci al  as it  yi el ds  m or e  e xt e nsi v e s af et y  a n d t ol er a bilit y  d at a, 
i n cr e as es  c o nfi d e n c e i n  effi c a c y  b y  c a pt uri n g  v ari a bilit y i n r es p o ns e  a n d  e x p os ur e,  w hil e 
pr o vi di n g  d at a t h at is  m or e  g e n er ali z a bl e f or l at er  p h as e tri als.   As s u c h,  a n  a d diti o n al  2 0  p ati e nts 
will  b e  e nr oll e d i nt o t h e  6 0  µ g   C o h ort.   T h es e  a d diti o n al s u bj e cts  will  pr o vi d e si g nifi c a ntl y  m or e 
s af et y d at a  at t h e  6 0  µ g   d os e,  b ut  als o  a  gr e at er i m b al a n c e  wit h r es p e ct t o  pl a c e b o ( p o ol e d  a cr oss 
c o h orts)  u n d er t h e  ori gi n al  4: 1 r a n d o mi z ati o n r ati o ( B X C L 5 0 1: pl a c e b o).   A c c or di n gl y, t o 
f a cilit at e  m or e i nf or m ati v e  c o m p aris o ns t o  pl a c e b o, t h e  a d diti o n al  2 0 s u bj ects  will  b e 
r a n d o mi z e d  at  a  1: 1 r ati o  of  B X C L 5 0 1: pl a c e b o.  T his  a c hi e v es t h e  o v er all r a n d o mi z ati o n r ati o  as 
ori gi n all y  d esi g n e d. 
F ort y -si x  pati e nts i n  P art  B  of t his st u d y  will  b e  r a n d o mi ze d  i n a  1: 1 r ati o t o r e c ei v e  B X C L 5 0 1 
4 0  µ g  or  m at c hi n g  pl a c e b o  fil m. 
Eli gi bl e  p ati e nts (t h os e  wit h  a n y t y p e  of  d e m e nti a)  m a y  b e i d e ntifi e d  i n s kill e d  n ursi n g f a ciliti es , 
m e nt al  h e alt h,  ps y c hi atri c  or  m e di c al  e m er g e n c y s er vi c es i n cl u di n g  m e di c al/ ps y c hi atri c 
o bs er v ati o n  u nits,  or  as  n e wl y  a d mitt e d t o  a  h os pit al s etti n g f or  a c ut e  a git ati o n  or  alr e a d y i n 
h os pit al f or  c hr o ni c  u n d erl yi n g  c o n diti o ns.   S u bj e cts  will r e m ai n i n t h eir f a cilit y  w hil e 
u n d er g oi n g s cr e e ni n g  pr o c e d ur es t o  ass ess  eli gi bilit y. 
P ati e nts i n  P art  B  of t his st u d y  will  b e  s e ni ors  a g e  6 5  a n d  a b o v e,  w h o  ar e s e mi-i nd e p e n d e nt,  a n d 
a bl e t o  c arr y  o ut  m a n y  of t h eir  a cti viti es  of  d ail y li vi n g  u n d er  mi ni m al s u p er visi o n, s u c h  as t h os e 
w h o r esi d e  i n  assist e d li vi n g f a ciliti es. 
T h e st u d y  will  c o nsist  of  a  pr e-s cr e e ni n g/s cr e e ni n g  p eri o d, tr e at m e nt  p eri o d,  a n d  a f oll o w- u p 
p eri o d.   E v al u ati o n  of  3  d os es  of  3 0  µ g,  6 0  µ g,  a n d  9 0  µ g ( C o h ort  1,  C o h ort  2,  a n d  C o h ort  3, 
r es p e cti v el y)  ar e  pl a n n e d,  wit h  a n  o pti o n t o t est  diff er e nt  d os es  b as e d  o n t ol er a bilit y  a n d s af et y. 
P r e -S c r e e ni n g  a n d  S c r e e ni n g  P e ri o d  
C o h ort  1  a n d  C o h ort  2 
D uri n g t h e s cr e e ni n g  p eri o d,  p ati e nts  assi g n e d t o  C o h ort  1  or  C o h ort  2  will  b e  ass ess e d f or t h eir 
eli gi bilit y  b y  u n d er g oi n g  Pr e- S cr e e ni n g  a n d  S cr e e ni n g  visit  ass ess m e nts  as  o utli n e d i n t h e 
S c h e d ul e  of  E v e nts ( T a bl e   3. 1).   T h e  Pr e- S cr e e ni n g  visit  m a y  o c c ur  n o  m or e t h a n  2 8  d a ys  b ef or e 
first  d os e  of st u d y tr e at m e nt. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 3  of  7 4  
C o h ort  3 
T h e  Pr e - S cr e e ni n g  visit  ass ess m e nts,  as  o utli n e d i n T a bl e   3. 1,  m ust  b e st art e d  wit hi n  2 8  d a ys 
b ef or e t h e first  d os e  of st u d y tr e at m e nt.   Aft er  c o m pl eti o n  of t h e  Pr e- S cr e e ni n g  ass ess m e nts  a n d 
r e vi e w  of l a bs a n d  E C Gs, s u bj e cts  assi g n e d t o  C o h ort  3, if  eli gi bl e,  will  p arti ci p at e i n  a  1- w e e k 
s af et y  o bs er v ati o n.   D uri n g t his  1- w e e k s af et y  o bs er v ati o n  p eri o d, s u bj e cts  will r e c ei v e i n- p ati e nt 
s af et y  ass ess m e nts  as  o utli n e d  i n T a b l e  3. 2 t o  e v al u at e t h eir ris k f or f alli n g  a n d s y n c o p e  wit h 
t wi c e  d ail y  B P  a n d  ort h ost ati c  B P  m e as ur e m e nts,  a n d r e c or di n g  of i nst a n c es  of f alli n g  a n d 
s y n c o p e. 
At t h e  Pr e - S cr e e ni n g  visit, if  a s u bj e ct is  a  Hi g h  F all  Ris k ( > 1 3)  vi a t h e J o h ns  H o p ki ns  F all  Ris k 
ass ess m e nt, t h e y  will  b e  e x cl u d e d fr o m st u d y  p arti ci p ati o n  a n d r e- s cr e e n  will  n ot  b e  p er mitt e d.  
If  a s u bj e ct  h as  O H  o n  m or e t h a n  1 i nst a n c e i n t h e s a m e  d a y  d uri n g t h e  1-w e e k s af et y 
o bs er v ati o n  p eri o d, t h e y  will  b e  e x cl u d e d fr o m st u d y  p arti ci p ati o n.   F oll o wi n g t h e  1- w e e k s af et y 
o bs er v ati o n  p eri o d, s u bj e cts  will  c o m pl et e t h e  S cr e e ni n g  visit  as  o utli n e d i n  T a bl e   3. 1. 
P ati e nts i n  P art  B  of t his st u d y  will f oll o w t h e s a m e s c h e d ul e  of  e v e nts  as  o utli n e d i n t h e 
S c h e d ul e  of  E v e nts ( T a bl e   3. 1).   T h e  Pr e- S cr e e ni n g  visit  m a y  o c c ur  n o  m or e t h a n  2 8  d a ys  b ef or e 
first  d os e  of st u d y tr e at m e nt. 
T r e at m e nt  P e ri o d  
U p o n  c o nfir m ati o n  of  eli gi bilit y, s u bj e cts  will  b e r a n d o mi z e d  wit hi n t h eir  d os e  c o h ort t o r e c ei v e 
a si n gl e  3 0  µ g ,  6 0 µ g ,  or  9 0  µ g  d os e, r es p e cti v el y,  of  B X C L 5 0 1  or  pl a c e b o fil m. 
F or  P art  B  of t his st u d y, s u bj e cts  will  b e r a n d o mi z e d t o r e c ei v e  a si n gl e  d os e  of  B X C L 5 0 1  4 0  µ g 
of  or  m at c hi n g  pl a c e b o fil m. 
U p t o  1  h o ur  pri or t o  d osi n g,  pr e- d os e  vit al si g ns, i n cl u di n g  B P,  ort h ost ati c  B P,  will  b e  c oll e ct e d.  
If  O H is  o bs er v e d  or if  S B P  < 1 1 0  m m H g, t h e n t h e s u bj e ct  will  b e  h y dr at e d  a n d  d osi n g  will  b e 
d el a y e d  u ntil  O H is r es ol v e d.   E v er y  eff ort  will  b e  m a d e t o  k e e p t h e s u bj e ct sitti n g  or l yi n g  d o w n 
f or  at l e ast  2  h o urs  aft er  d osi n g. 
Aft er  pr e -d os e  vit als  h a v e  b e e n  c oll e ct e d,  a si n gl e  d os e  of  B X C L 5 0 1  or  pl a c e b o fil m  will  b e 
a d mi nist er e d s u bli n g u all y  b y t h e  p ati e nt if  a bl e  wit h i nstr u cti o ns fr o m  a n  u n bli n d e d st aff  m e m b er 
w h o  wi ll  n ot  p arti ci p at e i n  e v al u ati o n  of s af et y  or  effi c a c y.   T h e  dr u g fil m  will  b e r et ai n e d i n t h e 
s u bli n g u al  c a vit y  u ntil  diss ol v e d.   P arti ci p a nts  will  als o  b e  e v al u at e d f or l o c al irrit ati o n  ar o u n d 
t h e  ar e a  w h er e t h e fil m is  pl a c e d.   Effi c a c y  a n d s af et y  ass ess m e nts  will  b e  c o n d u ct e d  p eri o di c all y 
b ef or e  a n d  aft er  d osi n g.   T h e  n e xt  c o h ort  will  b e  d os e d  aft er  c o m pl eti n g  a c cr u al  of  m ost  pri or 
p a n els, i n  a c c or d  wit h r e g ul ar  o n g oi n g  p eri o di c s af et y  a n d  P K r e vi e w  as  eli gi bl e s u bj e cts  ar e 
assi g n e d,  d os e d,  a n d  d at a  b e c o m es  a v ail a bl e.  
Vit al si g ns  a n d  E C Gs  will  b e  c o n d u ct e d  at t h e ti m e  p oi nts i n di c at e d i n t h e s c h e d ul e  of  e v e nts.  
P arti ci p a nts  will  b e  all o w e d  w at er  as  d esir e d  1 5  mi n ut es  aft er  c o m pl eti o n  of  d osi n g.   S af et y  a n d 
t ol er a bilit y  ass ess m e nts  will  b e  c o nti n u e d  u ntil t h e  m or ni n g  of  D a y  3  a n d  will  b e r e p e at e d  o n 
D a y  7   +  2  d a ys.  S m o ki n g  will  b e  p er mitt e d  a c c or di n g t o t h e sit e’s  p oli ci es.   Aft er t h e  4   h o ur 
ass ess m e nts  ar e  c o m pl et e d,  at t h e  dis cr eti o n  of t h e  PI, r es c u e t h er a p y  m a y  b e i niti at e d  usi n g 
st a n d ar d  of  c ar e tr eat m e nt  w hi c h  m a y i n cl u d e l or a z e p a m  0. 5- 5  m g  p o/I M  or  a n  a nti ps y c h oti c 
m e di c ati o n  p o/I M. 
A n y  a b n or m al  vit al si g n  m e as ur e m e nt,  cli ni c al l a b or at or y t est,  p h ysi c al  e x a mi n ati o n fi n di n g,  or 
E C G  p ar a m et er  d e e m e d  cli ni c all y si g nifi c a nt  b y t h e i n v esti g at or  will  b e  r e p e at e d, i n cl u di n g t est 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 4  of  7 4  
r es ults  o bt ai n e d  o n t h e fi n al st u d y  d a y  or  u p o n  e arl y t er mi n ati o n.   F or  a n y t est  a b n or m alit y 
d e e m e d  cli ni c all y si g nifi c a nt, r e p e at  a n al ysis  will  b e  p erf or m e d  d uri n g t h e f oll o w - u p  p eri o d  a n d 
u ntil t h e  v al u e r et ur ns t o  b as eli n e ( or  w it hi n  n or m al li mits)  or t h e i n v esti g at or  d e e ms t h e 
a b n or m alit y t o  b e  of  n o  cli ni c al si g nifi c a n c e.   S u bj e cts  pr es e nti n g  wit h  a  cli ni c all y si g nifi c a nt 
u ri n ar y tr a ct i nf e cti o n ( U TI)  as  d et er mi n e d  b y  cli ni c al l a b or at or y t ests  will  b e  e x cl u d e d fr o m t h e 
st u d y. 
A  n urs e  will  b e  pr es e nt  pri or t o  d osi n g  a n d r e m ai n  pr es e nt f or  at l e ast  6  h o urs  aft er  d osi n g  or 
l o n g er if  n e e d e d,  u ntil  a n y s af et y  c o n c er ns, i nt ol er a bilit y  or  a d v ers e  e v e nts r es ol v e.  If  d os e-
li miti n g s af et y  or i nt ol er a bilit y is  d et er mi n e d, f urt h er  d osi n g  of  a  c o h ort  m a y  b e st o p p e d,  a n d 
es c al ati o n  dis c o nti n u e d. 
T h e  P K  pl as m a s a m pl es s h o ul d  b e  c oll e ct e d  p er t h e  S c h e d ul e  of  E v e nts ( T a bl e   3. 1). 
T his is  a n  a d a pti v e  d esi g n  as  d os es s el e ct e d f or t esti n g  m a y  b e  diff er e nt fr o m t h es e,  b as e d  u p o n 
s af et y r e vi e ws.   D os es l o w er  or  hi g h er  m a y  b e  c h os e n t o t est,  a n d r e p e at e d,  u p t o  1 8 0  µ g  wit hi n 
e a c h  c o h ort ,  a n d  a d diti o n al s u bj e cts  m a y  b e  a d d e d t o  a  c o h ort.   B X C L 5 0 1 fil ms  m a y  b e  di vi d e d 
i n  h alf if  n e e d e d t o  d eli v er  h alf- d os e str e n gt hs.   E x c e pt f or  C o h ort  1,  e a c h s u bs e q u e nt  d os e l e v el 
will  b e  a ut h ori z e d  aft er  a s af et y r e vi e w  of t h e  pr e vi o us  d osi n g  c o h ort.   D osi n g  m a y  b e r e p e at e d 
i n t h e  c as e  of  p ersist e nt  or r e c urr e nt  a git ati on, if t h er e is  n o si g nifi c a nt i m pr o v e m e nt ( C GI- I  of  1 
or  2  as  “ v er y  m u c h ”  or  “ m u c h i m pr o v e d ”)  a n d  n o s af et y  e v e nts  e vi d e nt.   D osi n g  m a y  b e r e p e at e d 
u p t o  a t ot al  of t w o r e p e at  d os es ( at t h e s a m e r a n d o mi z ati o n  gr o u p  B X C L 5 0 1: pl a c e b o) f or  all 
c o h orts  e x c e pt f or  9 0  µ g  d os e  w hi c h  c a n  o nl y  b e r e p e at e d  o n c e (t ot al  1 8 0  µ g) if  n e c ess ar y,  at  2 
h o urs  p ost first  d os e  b ut  o nl y  aft er t h e  2  h o ur  ass ess m e nts  ar e  c o n d u ct e d  a n d  o nl y  wit hi n  1 2 
h o urs  p ost first  d os e.   P ati e nts  c a n  o nl y  b e r e- d os e d if t h e y  ar e  h e m o d y n a mi c all y st a bl e,  n ot 
h y p ot e nsi v e ( m ust  b e  gr e at er t h a n  9 0/ 6 0  di ast oli c/s yst oli c)  a n d  n ot  br a d y c ar di c ( m ust  b e  gr e at er 
t h a n  6 0  b p m).   P ati e nts  als o  c a n n ot  b e r e- d os e d if t h e y  ar e  ort h ost ati c ( a  dr o p  of  2 0  p oi nts i n 
eit h er  S B P  or  D B P)  or if t h e y  ar e  e x p eri e n ci n g  a n  A E.   N ot  o nl y  d o es t his  d et er mi n e i n di vi d u al 
r es p o ns e t o  a si n gl e  d os e,  b ut it  als o  d et er mi n es if  a  gi v e n s u bj e ct is r es p o nsi v e t o  a s e c o n d  d os e 
a n d  m a y r es p o n d t o  a  gr e at er  d os e,  or  c o ul d  b e  c at e g ori z e d  as  a  n o n-r es p o n d er t o  B X C L 5 0 1 
d es pit e  b ei n g  e x p os e d t o  a  gr e at er t ot al  d os e.  
S o m e s u bj e cts  m a y  b e  as k e d t o  p arti ci p at e i n t h e  o pti o n al s u b-st u d y i n  A P P E N DI X  A . 
P eri o di c s af et y  d at a r e vi e ws  will  b e  u n d ert a k e n  o n  a n  o n g oi n g  b asis t o r e vi e w  all s u bj e cts 
assi g n e d  a n d  d os e d,  as  d at a  a n d  a n al ys es  b e c o m e  a v ail a bl e.   D os e  es c al ati o n  will  b e  all o w e d 
u nl ess  a s af et y  or t ol er a bilit y iss u e  b e c o m es  e vi d e nt  u p o n  p eri o di c r e g ul ar s af et y r e vi e w. 
P ati e nts  e nr olli n g  at  a sit e  ar e s e q u e nti all y  assi g n e d t o t h e l o w est  d os e  c o h ort (i n cl u di n g  pl a c e b o) 
f oll o w e d  b y  e nr oll m e nt  assi g n m e nt t o i n cr e asi n g  d os e  c o h orts.   T his s e q ue nti al  es c al ati n g 
a d a pti v e  e nr oll m e nt  e ns ur es s u bj e ct s af et y; t h e l o w est  d os e  c o h ort  c o m pl et es  a c cr u al first,  hi g h er 
d os e  c o h orts  c o m pl et e l ast.  I n  a d diti o n, t h os e s u bj e cts  ass ess e d  as r e q uiri n g  a s e c o n d  d os e f or 
effi c a c y  pr o vi d e  e arl y  e vi d e n c e  of s af et y/ t ol er a bilit y  of  hi g h er  d os es  as t h e y  ar e  eff e cti v el y 
e x p os e d t o  d os es t h at  a p pr o xi m at e t h e  n e xt  d os e  c o h ort.   T h e  m aj orit y  of  p ati e nts  will  b e 
e nr oll e d  a n d  e v al u at e d i n l o w er  d os e  c o h orts  b ef or e  a  hi g h er  d os e  c o h ort is i niti at e d.   F urt h er, if 
e vi d e n c e  of i nt ol er a bilit y  aris es fr o m  a n al ys es i nt e gr ati n g  P K,  e x p os ur e  a n d s af et y/t ol er a bilit y  of 
all s u bj e cts  a n d  d os es, t h e  d os e r e gi m e n  m a y  b e  alt er e d,  or  a  diff er e nt  d os e  m a y  b e s el e ct e d t o 
t est t h e  h y p ot h esis t h at  a (t y pi c all y l o w er)  d os e r e gi m e n is  b ett er t ol erat e d.  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 5  of  7 4  
I n  a d diti o n t o  p eri o di c  o n g oi n g s af et y r e vi e ws,  aft er  a c cr ui n g  e a c h  d os e  c o h ort  a s af et y  a n d 
t ol er a bilit y r e vi e w  will  b e  d o n e  b y t h e  Bi o X c el  T h er a p e uti cs, I n c.  m e di c al  m o nit or,  cli ni c al 
p h ar m a c ol o gist,  a n d t h e  PI’s ( bli n d e d),  w h o  will  d e ci d e t o  c o nti n u e  or  m a y st o p t h e st u d y.  If 
d os e-li miti n g s af et y  or i nt ol er a bilit y is  d et er mi n e d, f urt h er  d osi n g  of  a  c o h ort  m a y  b e st o p p e d, 
a n d  es c al ati o n  dis c o nti n u e d. 
F urt h er  assi g n m e nt t o t h e s a m e  d os e  will  b e  h alt e d,  a n d  es c al ati o n  will  b e  dis c o nti n u e d f or t h e 
f oll o wi n g  dr u g-r el at e d  a d v ers e  e v e nts ( d os e-li miti n g t o xi cit y,  D L T)  cl assifi e d  b y  C T C A E 
v ersi o n  5. 0; 
•   O n e  Gr a d e  3  or  gr e at er  c ar di o v as c ul ar  e v e nt ( e. g., s y m pt o m ati c si n us  br a d y c ar di a t h at 
r e q uir es i n v asi v e i nt er v e nti o n) 
•   T hr e e  Gr a d e  2  c ar di o v as c ul ar  e v e nts ( e. g .,  a si g nifi c a nt  c ar di o v as c ul ar  e v e nt w hi c h  w as 
b ot h s y m pt o m ati c  a n d  r e q uir e d tr e at m e nt  wit h a n  a cti v e  p h ar m a c ol o gi c  i nt er v e nti o n 
(r e q uir e d I M/I V  m e di c ati o n  a d mi nistr ati o n i n  a d diti o n t o st a n d ar d s u p p orti v e  c ar e/ 
o bs er v ati o n/ m o nit ori n g/ h y dr ati o n). 
•   T hr e e  Gr a d e  3  or  gr e at er s e d ati o n  e v e nts ( d e pr ess e d l e v el  of  c o ns ci o us n ess  w h er e s u bj e ct 
is  diffi c ult t o  ar o us e,  or s o m n ol e n c e t o t h e  p oi nt  of  o bt u n d ati o n  or st u p or).   F or  D L T 
e v e nts r e p ort e d i n s u bj e cts  w h o r e c ei v e d  a s e c o n d  d os e, s p o ns or  m a y  el e ct t o  alt er t h e 
d os e r e gi m e n ( e. g., r e p e at e d  d osi n g  m a y  b e  dis c o nti n u e d  or  all o w e d  o nl y  aft er  a n  el a ps e d 
ti m e)  a n d  c o nti n u e t o  a c cr u e s u bj e cts  or i niti at e  a  diff er e nt  d os e t o t est t h e  h y p ot h esis t h at 
a l o w er  d os e r e m ai ns s af e  a n d  w ell t ol er at e d . 
A Es  of  m o d er at e s o m n ol e n c e,  e x c essi v e sl e e pi n ess  a n d  dr o wsi n ess  will  b e  c o nsi d er e d  a c c e pt a bl e 
f or t h e  c o n diti o n  as t h es e  m a y  b e  c o nsi d er e d  p art  of t h e  n at ur al  c o urs e  of r e c o v er y fr o m  a git ati o n 
a n d/ or  a  c o ns e q u e n c e  of  a n  a d e q u at e tr e at m e nt i nt er v e nti o n. 
D os e s el e cti o n  crit eri o n  ar e  d e p e n d e nt  u p o n t h e  e m er g e nt s af et y  a n d t ol er a bilit y  as  w ell  as 
cli ni c al  eff e cti v e n ess.   B e c a us e t h es e  e a c h r e m ai n t o  b e t est e d,  crit eri a f or  d os e s el e cti o n  m a y  b e 
a d a pt e d  as  d at a is  a c q uir e d ( e. g.,  e vi d e n c e  of r o b ust  effi c a c y  at t h e l o w est t est e d  d os e  c o ul d  s hift 
l o w  d os e  crit eri o n t o  a  hi g h er  pr o p orti o n f or  effi c a c y). 
F oll o w- u p  P e ri o d  
T h e  F oll o w- u p  P eri o d  will  e n c o m p ass t h e  D a y  2  F oll o w- U p  a n d t h e  D a y  3  visits  as  d et ail e d i n 
T a bl e   3. 1. 
S u bj e cts  will  als o  b e r e q uir e d t o  u n d er g o  a  D a y  7  E n d  of  St u d y  visit, i n  w hi c h t h e  C M AI,  P E C, 
a n d  P A S,  al o n g  wit h s af et y  ass ess m e nts,  will  b e  p erf or m e d. 
8. 2.   
St o p pi n g  C rit e ri o n  
T h e f oll o wi n g st o p pi n g  crit eri o n  will  b e  e m pl o y e d:  if  a  gi v e n  c o h ort  h as  2  dr u g- tr e at e d  p ati e nts 
e x p eri e n ci n g s y n c o p e  or  a si n gl e s y n c o p e r el at e d f all,  d osi n g  will  b e s us p e n d e d.   Aft er  a 
t h or o u g h  u n bli n d e d s af et y r e vi e w, t h e  c o h ort  m a y  b e st o p p e d,  a n d t esti n g  m a y  c o nti n u e  at t h e 
s a m e  or l o w er  d os e s el e ct e d  b as e d  o n t h e s af et y r e vi e w  ass ess m e nt.  
I n  P art  B  of t h e st u d y,  gi v e n t h at t h e  6 0 µ g  d os e  w as s af e  a n d  w ell t ol er at e d,  t h e st o p pi n g crit eri a  
is d e e m e d  u n n e c ess ar y  f or t h e  4 0  µ g  d os e. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 6  of  7 4  
8. 3.   
St u d y  Sit es  
T h e st u d y  will t a k e  pl a c e  at  a p pr o xi m at el y  4  c e nt ers i n t h e  U S. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 7  of  7 4  
9.   
S U B J E C T  P O P U L A TI O N  
9. 1.   
S el e cti o n  of  St u d y  P o p ul ati o n  
9. 1. 1.   
I n cl usi o n  C rit e ri a  
A s u bj e ct  will  b e  eli gi bl e f or i n cl usi o n i n t h e st u d y if  h e  or s h e  m e ets t h e f oll o wi n g  crit eri a:  
1.   M al e  a n d f e m al e  p ati e nts  6 5  y e ars  a n d  ol d er.  
2.   P ati e nts  w h o  h a v e  m et  D S M - 5  crit eri a f or  n e ur o c o g niti v e  dis or d er  or d e m e nti a  w h o  h a v e 
hist or y  of i nst a n c es  of  a c ut e  a git ati o n . 
3.   Hist or y  of  a git ati o n ( e. g.,  ki c k,  bit e, fl aili n g) t o t h e  p oi nt t h at it i m p airs s o ci al  a cti viti es, 
r e q uir es st affi n g,  or  m e di c al i nt er v e nti o n,  or i m p airs  a bilit y f or f u n cti o n al  a cti viti es  of 
d ail y li vi n g . 
4.   P ati e nts  w h o  m e et I P A  di a g n osti c  crit eri o n f or  a git ati o n.  
5.   P ati e nts  w h o  ar e j u d g e d t o  b e  cli ni c all y  a git at e d  at  Pr e -d os e  wit h  a t ot al s c or e  of  ≥ 8  o n 
t h e  4 it e ms ( a berr a nt  v o c ali z ati o n,  m ot or  a git ati o n,  a g gr essi v e n ess,  a n d r esisti n g  c ar e) 
c o m prisi n g t h e  P A S.  
6.   P ati e nts  w h o  h a v e  a  S c or e  of  ≥ 2  o n  at l e ast  1  of t h e  4 it e ms  o n t h e  P A S.  
7.   P ati e nts  w h o r e a d,  u n d erst a n d,  a n d  pr o vi d e  writt e n i nf or m e d  c o ns e nt,  or  w h o  h a v e  a 
L A R.  
8.   P ati e nts  w h o  ar e i n  g o o d  g e n er al  h e alt h  pri or t o st u d y  p arti ci p ati o n  as  d et er mi n e d  b y  a 
d et ail e d  m e di c al  hist or y,  p h ysi c al  e x a mi n ati o n,  1 2-l e a d  E C G,  bl o o d  c h e mistr y  pr ofil e, 
h e m at ol o g y,  a n d  uri n al ysis,  a n d i n t h e  o pi ni o n  of t h e  Pri n ci p al I n v esti g at or . 
9.   F e m al e  p arti ci p a nts, if  of  c hil d - b e ari n g  p ot e nti al  a n d s e x u all y  a cti v e,  a n d  m al e 
p arti ci p a nts, if s e x u all y  a cti v e  wit h  a  p art n er  of  c hil d - b e ari n g  p ot e nti al,  w h o  a gr e e t o  us e 
a  m e di c all y  a c c e pt a bl e  a n d  eff e cti v e  birt h  c o ntr ol  m et h o d t hr o u g h o ut t h e st u d y  a n d f or 
1  w e e k f oll o wi n g t h e  e n d  of t h e st u d y.   M e di c all y  a c c e pt a bl e  m et h o ds  of  c o ntr a c e pti o n 
t h at  m a y  b e  us e d  b y t h e  p arti ci p a nt  a n d/ or  his/ h er  p art n er i n cl u d e  a bsti n e n c e,  birt h  c o ntr ol 
pills  or  p at c h es,  di a p hr a g m  wit h s p er mi ci d e, I U D,  c o n d o m  wit h f o a m  or s p er mi ci d e, 
v a gi n al s p er mi ci d al s u p p osit or y, s ur gi c al st erili z ati o n ,  a n d  pr o g esti n i m pl a nt  or i nj e cti o n.  
Pr o hi bit e d  m et h o ds i n cl u d e: t h e r h yt h m  m et h o d,  wit h dr a w al,  c o n d o ms  al o n e,  or 
di a p hr a g m  al o n e.  
9. 1. 2.   
E x cl usi o n  C rit e ri a  
1.   F or  P art  B:    P ati e nts  w h o  h a v e  d e m e nti a  ass o ci at e d  wit h  P ar ki ns o n’s  dis e as e  a n d/ or  L e w y 
B o d y  Dis e as e, if  eti ol o g y  of  d e m e nti a is  k n o w n. 
2.   P ati e nts  wit h  a git ati o n  c a us e d  b y  a c ut e i nt o xi c ati o n  m ust  b e  e x cl u d e d.   P ositi v e 
i d e ntifi c ati o n  of  n o n- pr es cri pti o n  dr u gs  d uri n g  uri n e s cr e e ni n g  e x cl u d es t h e s u bj e ct.  
3.   P ati e nts tr e at e d  wit hi n  4  h o urs  pri or t o st u d y  dr u g  a d mi nistr ati o n  wit h  b e n z o di a z e pi n es, 
ot h er s e d ati v es,  h y p n oti cs,  or  a nti ps y c h oti cs  m ust  b e  e x cl u d e d . 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 8  of  7 4  
4.   Tr e at m e nt  wit h  al p h a - 1  n or a dr e n er gi c  bl o c k ers,  al p h a  a dr e n er gi c  a nt a g o nists  wit hi n 
8  h o urs  pri or t o  d osi n g.  
5.   N o  n e w  c hr o ni c  m e di c ati o ns i niti at e d i n t h e  p ast  1 4  d a ys  pri or t o s cr e e ni n g  e x cl u di n g 
o v er-t h e- c o u nt er  pr o d u cts t a k e n s p or a di c all y.  
6.   P ati e nts  wit h si g nifi c a nt ris k  of s ui ci d e  or  h o mi ci d e  p er t h e i n v esti g at or’s  ass ess m e nt,  or 
a n y  p ati e nt  wit h  a n  a ns w er  of  “ y es ” t o it e m  4  or  5  o n t h e  C- S S R S.  
7.   P ati e nts  w h o  h a v e  h y dr o c e p h al us, s ei z ur e  dis or d er,  or  hist or y  of si g nifi c a nt  h e a d tr a u m a, 
s u b ar a c h n oi d  bl e e di n g,  br ai n t u m or,  e n c e p h al o p at h y,  m e ni n gitis,  or f o c al  n e ur ol o gi c al 
fi n di n gs, wit h  a r e c e nt  l ar g e ( n o n- mi cr o v as c ul ar) str o k e  w h o  m a y  b e  c o nsi d er e d 
m e di c all y  u nst a bl e  or i n r e c o v er y  m ust  b e  e x cl u d e d.   P ati e nts  wit h  a r e m ot e  hist or y  of 
str o k e  m a y  b e i n cl u d e d, r e g ar dl ess  of si z e/l o c ati o n. 
8.   Hist or y  of  cli ni c all y si g nifi c a nt s y n c o p e  or s y n c o p al  att a c ks,  ort h ost ati c  h y p ot e nsi o n 
wit hi n t h e  p ast  2  y e ars,  c urr e nt  e vi d e n c e  of  h y p o v ol e mi a,  ort h ost ati c  h y p ot e nsi o n 
(f oll o wi n g  1,  3,  a n d  5  mi n ut es  of st a n di n g,  a  ≥ 2 0  m m H g  dr o p i n s yst oli c  B P  or  ≥ 1 0 
m m H g  dr o p i n  D B P,  or  di z zi n ess  or li g ht h e a d e d n ess) ,  br a d y c ar di a, or  b as eli n e  ( pr e- d os e) 
m e as ur e m e nts  of  h e art r at e  < 6 0   b p m,  S B P  < 1 1 0  m m H g,  or  D B P  < 7 0  m m H g  m ust  b e 
e x cl u d e d.  
N ot e :   S u bj e cts i n  C o h ort  3  w h o  h a v e  O H  o n  m or e t h a n  1 i nst a n c e i n t h e s a m e  d a y  d uri n g 
t h e  1- w e e k  o bs er v ati o n  p eri o d  m ust  b e  e x cl u d e d. 
9.   P ati e nts  wit h l a b or at or y  or  E C G  a b n or m aliti es ( e. g.,  a d v a n c e d  h e art  bl o c k [ s e c o n d-d e gr e e 
or  a b o v e  atri o v e ntri c ul ar  bl o c k  wit h o ut  p a c e m a k er ],  di a g n osis  of si c k si n us s y n dr o m e) 
c o nsi d er e d  cli ni c all y si g nifi c a nt  b y t h e i n v esti g at or  or  q u alifi e d  d esi g n e e  a n d t h at  w o ul d 
h a v e  cli ni c al i m pli c ati o ns f or t h e  p ati e nt's  p arti ci p ati o n i n t h e st u d y  m ust  b e  e x cl u d e d.  
1 0.  C o h ort  3  o nl y:   P ati e nts  w h o  ar e t a ki n g  nitr at es  or  b et a  bl o c k ers s h all  b e  e x cl u d e d.   A n y 
ot h er  a nti- h y p ert e nsi v es s h o ul d  b e  m ai nt ai n e d i n t h e  c o urs e  of t h e st u d y. 
1 1.  P ati e nts  wit h s eri o us,  u nst a bl e,  or  u n c o ntr oll e d  m e di c al ill n ess es  m ust  b e  e x cl u d e d.  
T h es e i n cl u d e  c urr e nt  m o d er at e t o s e v er e  h e p ati c i m p air m e nt,  or r e n al,  g astr o -
e nt er ol o gi c, r es pir at or y,  c ar di o v as c ul ar (i n cl u di n g is c h e mi c  h e art  dis e as e,  c o n g esti v e 
h e art f ail ur e),  e n d o cri n ol o gi c,  or  h e m at ol o gi c  dis e as e.  
1 2.  P ati e nts  w h o  h a v e r e c ei v e d  a n i n v esti g ati o n al  dr u g  wit hi n  3 0  d a ys  pri or t o t h e  c urr e nt 
a git ati o n  e pis o d e  m ust  b e  e x cl u d e d.  
1 3.  P ati e nts  w h o  ar e  c o nsi d er e d  b y t h e i n v esti g at or, f or  a n y r e as o n, t o  b e  a n  u ns uit a bl e 
c a n di d at e f or r e c ei vi n g  d e x m e d et o mi di n e,  or  u n a bl e t o  us e t h e s u bli n g u al fil m,  m ust  b e 
e x cl u d e d,  e. g.,  p ati e nts  wit h  a  hist or y  of  all er gi c r e a cti o ns t o  d e x m e d et o mi di n e. 
1 4.  P ati e nts  e x p eri e n ci n g  cli ni c all y si g nifi c a nt  p ai n,  p er i n v esti g at or. 
1 5.  C o h ort  3  o nl y:   P ati e nts  w h o  ar e  a  hi g h f all ris k  ass ess e d  vi a t h e J o h ns  H o p ki ns  F all  Ris k 
Ass ess m e nt (t ot al s c or e  > 1 3)  or  d uri n g t h e  1- w e e k s af et y  o bs er v ati o n  p eri o d  will  b e 
e x cl u d e d fr o m f urt h er st u d y  p arti ci p ati o n. 
1 6.  Pr e g n a n c y. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  3 9  of  7 4  
9. 2.   
R e m o v al  of  S u bj e cts f r o m  T h e r a p y  o r  Ass ess m e nt  
All s u bj e cts  ar e fr e e t o  wit h dr a w fr o m  p arti ci p ati o n i n t his st u d y  at  a n y ti m e f or  a n y r e as o n  a n d 
wit h o ut  pr ej u di c e. 
T h e i n v esti g at or  m a y t er mi n at e  d osi n g f or  a s u bj e ct  at  a n y ti m e f or l a c k  of t h er a p e uti c  eff e ct, 
i nt ol er a bilit y t o t h e s u bj e ct or  u n a c c e pt a bl e  A Es, i nt er c urr e nt ill n ess,  n o n c o m pli a n c e  wit h st u d y 
pr o c e d ur es,  a d mi nistr ati v e r e as o ns,  or  u ns uit a bilit y f or t h e st u d y i n t h e i n v esti g at or’s  o pi ni o n t o 
pr ot e ct t h e s u bj e ct’s  b est i nt er est.  
If  a s u bj e ct is  wit h dr a w n fr o m  d osi n g  b ef or e  c o m pl eti n g t h e st u d y, t h e r e as o n f or  wit h dr a w al  will 
b e  e nt er e d  o n t h e  a p pr o pri at e  c as e r e p ort f or m ( C R F).   W h e n e v er  p ossi bl e  a n d r e as o n a bl e, 
e v al u ati o ns t h at  w er e s c h e d ul e d f or st u d y  c o m pl eti o n s h o ul d  b e  p erf or m e d  at t h e ti m e  of 
pr e m at ur e  dis c o nti n u ati o n  of  d osi n g.   S u bj e cts  w h o  dis c o nti n u e fr o m t h e st u d y  will  n ot  b e 
r e pl a c e d. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 0  of  7 4  
1 0.   
S T U D Y  T R E A T M E N T S  
1 0. 1.   
M et h o d  of  Assi g ni n g  S u bj e cts t o  T r e at m e nt  G r o u ps  
U p o n  c o nfir m ati o n  of  eli gi bilit y f oll o wi n g s cr e e ni n g  ass ess m e nts,  p ati e nts  will  b e r a n d o mi z e d t o 
B X C L 5 0 1  or  pl a c e b o fil m. 
I n  e a c h  of t h e  3  d os e  c o h orts,  p ati e nts  will  b e r a n d o mi z e d i n  a  4: 1 r ati o  of  B X C L 5 0 1: pl a c e b o.  
H o w e v er,  aft er  b e gi n ni n g  e nr oll m e nt i n t h e  9 0  µ g   C o h ort ,  a  d e cisi o n  w as  m a d e  n ot t o  c o nti n u e 
t o  e nr oll ,  b ut r at h er t o  e nr oll  a n  a d diti o n al  2 0 s u bj e cts i n t h e  60  µ g  .   T his  will r es ult i n 
si g nifi c a ntl y  m or e s af et y  d at a  at t h at  d os e,  b ut  als o  a  gr e at er i m b al a n c e  wit h r es p e ct t o  pl a c e b o 
( p o ol e d  a cr oss  c o h orts)  u n d er t h e  ori gi n al  4: 1 r a n d o mi z ati o n r ati o ( B X C L 5 0 1: pl a c e b o).  
A c c or di n gl y, t o f a cilit at e  m or e i nf or m ati v e   c o m p aris o ns t o  pl a c e b o, t h e  a d diti o n al  2 0 s u bj e cts 
will  b e r a n d o mi z e d  at  a  1: 1 r ati o  of  B X C L 5 0 1: pl a c e b o.   T his  a c hi e v es t h e  o v er all r a n d o mi z ati o n 
r ati o  as  ori gi n all y  d esi g n e d. 
I n  P art  B, th e  i n cl usi o n  of  a n  a d diti o n al  4 6 s u bj e cts will  ass ess t h e  effi c a c y  a n d s af et y  of  a 
4 0  µ g   d os e  of  B X C L 5 0 1  or  pl a c e b o i n  a  1: 1 r a n d o mi z ati o n r ati o. 
St u d y r a n d o mi z ati o n  will  b e  c o m p ut er  g e n er at e d. 
1 0. 2.   
I d e ntifi c ati o n  of I n v esti g ati o n al  P r o d u ct  
B X C L 5 0 1  will  b e  pr o vi d e d  as  a s m all, s oli d- d os e fil m f or m ul ati o n,  a p pr o xi m at el y  2 2  m m  × 
1 3  m m,  a n d l ess t h a n  1  m m t hi c k,  d esi g n e d t o i m m e di at el y  a d h er e t o t h e  S L  m u c os a  a n d t o 
s ol u bili z e i n  1-2  mi n ut es.  
B X C L 5 0 1  S u bli n g u al  Fil m  6 0  µ g,  a n d  pl a c e b o  ar e  p a c k a g e d  as i n di vi d u al fil ms i n  h e at- s e al e d 
w hit e f oil  p o u c h es  wit h  a l a b el.   T h e  p o u c h  h as  a  w hit e  c ol or e d  o ut er l a y er  wit h f oil  c ol or e d 
i n n er l a y er.  I n di vi d u al fil m  a p p e ar a n c e is  as f oll o ws: 
•   6 0  µ g  –  gr e e n r e ct a n g ul ar t hi n fil m ( ~ 2 2  m m  ×  1 2. 8  m m)  wit h  2  bl u e s p ots 
•   Pl a c e b o  –  gr e e n r e ct a n g ul ar t hi n fil m ( ~ 2 2  m m  ×  1 2. 8  m m)  wit h  or  wit h o ut  2  bl u e s p ots 
I n  a d diti o n t o t h es e fil ms,  1 2 0 µ g   gr e e n r e ct a n g ul ar t hi n fil ms ( ~ 2 2  m m  ×  1 2. 8  m m)  wit h 
2  d ar k er  c ol or e d s p ots  a n d  1 8 0  µ g  gr e e n r e ct a n g ul ar t hi n fil ms ( ~ 2 2  m m  ×  1 2. 8  m m)  wit h 
2  d ar k er  c ol or e d s p ots  m a y  b e  pr o vi d e d t o t h e sit es  a n d  a d mi nist er e d  as  a p pr o pri at e. 
F or  P art  B  of t h e st u d y,  B X C L 5 0 1  S u bli n g u al  Fil m  8 0  µ g,  a n d  pl a c e b o  ar e  p a c k a g e d  as 
i n di vi d u al fil ms i n  h e at-s e al e d  w hit e f oil  p o u c h es  wit h  a l a b el.   T h e  p o u c h  has  a  w hit e  c ol or e d 
o ut er l a y er  wit h f oil  c ol or e d i n n er l a y er.  I n di vi d u al fil m  a p p e ar a n c e is  as f oll o ws: 
•   8 0  µ g  –  gr e e n r e ct a n g ul ar t hi n fil m ( ~ 2 2  m m  ×  1 2. 8  m m)  wit h  2  bl u e s p ots 
•   Pl a c e b o  –  gr e e n r e ct a n g ul ar t hi n fil m ( ~ 2 2  m m  ×  1 2. 8  m m)  wit h  or  wit h o ut  2  bl u e s p ots 
Bi o X c el  T h er a p e uti cs, I n c.  will  pr o vi d e  a n  a d e q u at e s u p pl y  of st u d y  dr u g t o t h e sit es. 
1 0. 3.   
T r e at m e nt  A d mi nist r ati o n  
D osi n g  m a y  b e  a c hi e v e d  b y  c utti n g  of  a fil m,  wi dt h wis e,  dir e ctl y i n t h e  mi d dl e, t o  m a k e  a  h alf 
d os e.   D osi n g  m a y  als o  b e  a c hi e v e d  b y  a d m i nistr ati o n  of  1 t o  2 fil ms ( e. g.,  a  1 2 0  µ g  d os e  m a y  b e 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 1  of  7 4  
c ut i n  h alf  a n d  a d mi nist er e d t o  m a k e  a  6 0  µ g   d os e  or  a  1 8 0 µ g   d os e  m a y  b e  c ut i n  h alf  a n d 
a d mi nist er e d t o  m a k e  a  9 0  µ g   d os e).   At t h e  b e gi n ni n g  of  e a c h st u d y s essi o n,  p ati e nts  will  b e 
i nstr u ct e d  o n  h o w t o s elf-a d mi nist er t h e i n v esti g ati o n al  pr o d u ct.  If t h e  p ati e nt  c a n s elf -
a d mi nist er,  h e/s h e  will s elf - a d mi nist er t h e  d os e  of  B X C L 5 0 1  or  pl a c e b o fil m s u bli n g u all y  u n d er 
s u p er visi o n  of  a n  u n bli n d e d st aff  m e m b er  w h o  will  n ot  p arti ci p at e i n  e v al u ati o n  of s af et y  or 
effi c a c y.   T h e i n v esti g ati o n al  pr o d u ct  will  b e r et ai n e d i n t h e s u bli n g u al  c a vit y  u ntil  diss ol v e d.  If 
s u bli n g u al  a d mi nistr ati o n is  n ot  p ossi bl e, t h e fil m  m a y  b e  pl a c e d  i nsi d e t h e l o w er li p.   T h e 
l o c ati o n  of t h e  pl a c e m e nt  of t h e fil m s h o ul d  b e  n ot e d i n t h e s u bj e ct’s  c h art.   O bj e cti v e  b u c c al 
m u c os al  e x a mi n ati o n  a n d ti m e  of fil m  diss ol uti o n  b y  u n bli n d e d st u d y st aff  p er  T a bl e   3. 1 will  b e 
c o n d u ct e d. 
I n  P art  B,  d osi n g  will  b e  a c hi e v e d  b y  c utti n g  of  a n  8 0 µ g  fil m,  wi dt h wis e,  dir e ctl y i n t h e  mi d dl e, 
t o  m a k e  a 4 0  µ g  d os e. 
1 0. 4.   
St o r a g e  
B X C L 5 0 1  p a c k a g e d fil ms  m ust  b e st or e d  at r o o m t e m p er at ur e ( 2 0 - 2 5 ° C  wit h  all o w e d  e x c ursi o n 
of  1 5- 3 0 ° C).   St or e i n t h e  ori gi n al  p a c k a g e. 
1 0. 5.   
L a b eli n g  
E a c h  c o nt ai n er  of st u d y  dr u g  will  b e l a b el e d  wit h st u d y s p e cifi c i nf or m ati o n t h at  m e ets  all 
a p pli c a bl e r e g ul at or y r e q uir e m e nts.  
1 0. 6.   
D r u g  A c c o u nt a bilit y  
T h e i n v esti g at or  m ust  m ai nt ai n  a d e q u at e r e c or ds s h o wi n g t h e r e c ei pt,  dis p e nsi n g, r et ur n,  or  ot h er 
dis p ositi o n  of st u d y  dr u g, i n cl u di n g t h e  d at e,  q u a ntit y,  b at c h  or  c o d e  n u m b er,  a n d i d e ntifi c ati o n 
of s u bj e cts (s u bj e ct  n u m b er  a n d i niti als)  w h o r e c ei v e d st u d y  dr u g.   T h e i n v esti g at or  will  n ot 
s u p pl y st u d y  dr u g t o  a n y  p ers o n  e x c e pt t h os e  n a m e d  as s u b-i n v esti g at ors  o n t h e  F D A  1 5 7 2, 
d esi g n at e d st aff,  a n d s u bj e cts i n t his st u d y.   T h e i n v esti g at or  will  n ot  dis p e ns e st u d y  dr u g fr o m 
a n y sit es  ot h er t h a n t h os e list e d  o n t h e  F D A  1 5 7 2.   St u d y  dr u g  m a y  n ot  b e r el a b el e d  or 
r e assi g n e d f or  us e  b y  ot h er s u bj e cts. 
U p o n  c o m pl eti o n  of t h e st u d y,  u n us e d s u p pli es  of st u d y  dr u g  will  b e r e c o n cil e d  b y t h e 
i n v esti g at or  a n d r et ur n e d t o t h e s p o ns or  or  d estr o y e d  as  dir e ct e d. 
1 0. 7.   
Bli n di n g  a n d  U n bli n di n g  T r e at m e nt  Assi g n m e nt  
T his st u d y  will  b e  c o n d u ct e d  u n d er  d o u bl e- bli n d  c o n diti o ns s o t h at  n eit h er t h e s u bj e ct  n or t h e 
I n v esti g at or  or st u d y st aff  m e m b ers  will  k n o w t h e i d e ntit y  of  e a c h s u bj e ct’s tr e at m e nt.  
B X C L 5 0 1  or  pl a c e b o fil m  will  b e  pr o vi d e d  a n d  a d mi nist e r e d  p er  S e cti o n 1 0. 3   of t his  pr ot o c ol. 
Tr e at m e nt  assi g n m e nt f or  a n i n di vi d u al s u bj e ct s h o ul d  b e  u n bli n d e d  o nl y i n  a n  e m er g e n c y,  w h e n 
k n o wl e d g e  of t h e tr e at m e nt  assi g n m e nt is  ur g e ntl y  n e e d e d f or t h e  cli ni c al  m a n a g e m e nt  or 
w elf ar e  of t h e s u bj e ct.    T h e I n v esti g at or s h o ul d  c o nt a ct t h e  m e di c al  m o nit or  or  pr oj e ct  m a n a g er 
b ef or e  u n bli n di n g,  w h e n  p ossi bl e,  b ut  pri orit y s h o ul d  b e  gi v e n t o tr e at m e nt  of t h e s u bj e ct.   If 
u n bli n di n g  o c c urs  wit h o ut  pri or  a p pr o v al, t h e i n v esti g at or s h o ul d  pr o m ptl y  c o m m u ni c at e t h e 
cir c u mst a n c es l e a di n g t o t h e  u n bli n di n g  b y t el e p h o n e  a n d i n  writi n g t o t h e  m e di c al  m o nit or. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 2  of  7 4  
Br e a ki n g  of t h e  bli n d,  ot h er t h a n  as  d es cri b e d  a b o v e,  will  b e  c o nsi d er e d  a  pr ot o c ol  vi ol ati o n.   F or 
a n y s u bj e ct  w h os e st u d y  dr u g tr e at m e nt is  u n bli n d e d, t h e  d at e, ti m e,  a n d r e as o n f or t h e 
u n bli n di n g  m ust  b e  d o c u m e nt e d. 
1 0. 8.   
S el e cti o n  of  D os e i n t h e  St u d y  
Pr e vi o us  cli ni c al st u di es  wit h t h e s u bli n g u al fil m,  d es cri b e d  a b o v e i n  S e cti o n  6. 2 ,  pr o vi d e  dir e ct 
e vi d e n c e t h at t h e  e x p os ur es fr o m t h e fil m  ar e s u bst a nti all y l o w er t h a n t h os e  a c hi e v e d  wit h t h e 
a p pr o v e d i ntr a v e n o us f or m ul ati o n.  I n tr a nsl ati o n al  pr o of  of  c o nfi d e n c e st u di es  usi n g I V 
d e x m e d et o mi di n e i n  h e alt h y  el d erl y  v ol u nt e ers,  a git at e d  p ati e nts  wit h s c hi z o p hr e ni a  as  w ell  as 
a git at e d  el d erl y  p ati e nts  wit h  d e m e nti a, I V i nf usi o n  a c hi e v e d  c al mi n g  eff e cts  wit h  e x p os ur es i n 
t h e r a n g e  of  pr o p os e d  d os es f or t his tri al ( 1 0 µ g  t o  1 8 0 µ g   B X C L 5 0 1).  I n  a git at e d  p ati e nts, mil d 
c al mi n g  eff e cts  b e c a m e   e vi d e nt  wit h  pl as m a  e x p os ur es t h at  e q u at e  wit h  a  2 0 µ g  t o  4 0 µ g  
B X C L 5 0 1  d os e.   A cr oss tr a nsl ati o n al st u di es  usi n g I V  a d mi nistr ati o n  a n d st u di es  d eli v eri n g 
d e x m e d et o mi di n e  vi a  B X C L 5 0 1, r el ati v e t o  a p pr o v e d I V  d e x m e d et o mi di n e  us e, l o w  e x p os ur e 
w as s af e  a n d  w ell -t ol er at e d  d e m o nstr ati n g  c al mi n g  eff e cts  wit h o ut  e x c essi v e s e d ati o n i n  a git at e d 
p o p ul ati o ns.   T h er e  w er e  als o  n o s eri o us  or s e v er e  a d v ers e  e v e nts,  or  cli ni c all y  m e a ni n gf ul 
c h a n g es i n  h e art r at e  or  bl o o d  pr ess ur e.  I n  St u d y  B X C L 5 0 1- 1 0 2  p ati e nts  wit h  a gi t ati o n 
ass o ci at e d  wit h s c hi z o p hr e ni a, si n gl e  d os es  u p t o  1 8 0  u g  w er e  a d mi nist er e d  wit h  n o s eri o us 
a d v ers e  eff e cts.    T h e  hi g h est  pr o p os e d t ot al  d ail y  d os e i n t h e  c urr e nt st u d y is  als o  1 8 0  u g,  b ut t h e 
st arti n g  d os e is  o nl y  3 0  u g,  w hi c h  pr o vi d es  a n  a d e q u at e s af et y  m ar gi n if t h e  P K, s af et y  a n d/ or 
t ol er a bilit y is s u bst a nti all y  diff er e nt i n t h e  d e m e nti a  p o p ul ati o n  c o m p ar e d t o t h e s c hi z o p hr e ni c 
p o p ul ati o n. 
A n al ysis  of t h e  3 0  a n d  6 0  µ g  c o h orts r e v e al e d  b ot h  d os es  w er e  w ell t ol er at e d  wit h t h e  6 0  µ g  d os e 
d e m o nstr ati n g  effi c a c y  vs.  pl a c e b o  o n  e a c h i n d e p e n d e nt  m e as ur e  of  a git ati o n.   Alt h o u g h  n ot 
r e a c hi n g st atisti c al si g nifi c a n c e, t h e  3 0  µ g  d os e  c h a n g es  p ar all el e d t h e st atisti c all y si g nifi c a nt 
r e d u cti o ns i n  a git ati o n  o bs er v e d f or t h e  6 0  µ g  d os e  gr o u p,  wit h  a  n u m eri c al i m pr o v e m e nt  v ers us 
pl a c e b o  o n t h e  P E C  a n d  P A S r ati n gs  o v er  8  h o urs.   As s u c h, t h e s p o ns or  d e ci d e d t o  e x pl or e 
effi c a c y  a n d s af et y  of  a  4 0  µ g  d os e  c o h ort  as  a n i nt er m e di at e  d os e  b et w e e n  3 0  µ g  a n d  6 0  µ g.  
T h e  o bj e cti v e  of  P art  B is t o t est  a  d os e  of  4 0  µ g  as  p ot e nti all y t h e l o w est s af e  d os e t h at r e m ai ns 
eff e cti v e  vs.  pl a c e b o i n r e d u ci n g  a git ati o n.  I n  a d diti o n, t h e  d at a  c oll e ct e d i n  P art  B  will  b e fr o m 
a l ar g er  n u m b er  of sit es  a n d r at ers  w hi c h  e n a bl es  a  m or e  a c c ur at e  esti m at e  of  v ari a n c e f or 
p o w eri n g f ut ur e  P h as e  3  d e v el o p m e nt st u di es. 
1 0. 9.   
T r e at m e nt  C o m pli a n c e  
Dr u g  a c c o u nt a bilit y  will  b e  p erf or m e d  b y sit e  p ers o n n el  a n d t h e  dr u g  a d mi nistr ati o n  c o m pli a n c e 
is  e x pe ct e d t o  b e  1 0 0 %. 
1 0. 1 0.   C o n c o mit a nt  M e di c ati o ns  
All  c o n c o mit a nt  m e di c ati o ns  us e d (i n cl u di n g  o v er-t h e- c o u nt er  m e di c ati o ns  a n d  h er b al  a n d 
n utriti o n al s u p pl e m e nts)  will  b e r e c or d e d i n t h e s o ur c e  d o c u m e nt  a n d  o n t h e  a p pr o pri at e  C R F.  
T h e  m e di c ati o n  n a m e,  d os e, fr e q u e n c y,  d at e,  a n d i n di c ati o n f or  us e  m ust  b e r e c or d e d  o n t h e 
C R F.   M e di c ati o ns  a n d t h er a pi es t h at  ar e  c o nsi d er e d  n e c ess ar y f or t h e s u bj e ct’s  w elf ar e  a n d  will 
n ot i nt erf er e  wit h t h e r es p o ns e t o t h e st u d y  m e di c ati o n  m a y  b e  gi v e n  at t h e  dis cr eti o n  of t h e 
i n v esti g at or. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 3  of  7 4  
1 0. 1 0. 1.   P e r mitt e d  T h e r a pi es  
C o n c o mit a nt  m e di c ati o ns  ar e  all o w e d ( u nl ess s p e cifi c all y  pr o hi bit e d)  b ut s h o ul d  b e li mit e d t o 
o nl y t h os e  m e di c ati o ns  c o nsi d er e d  n e c ess ar y.   S m o ki n g is  all o w e d  a c c or di n g t o t h e sit e  p oli ci es. 
R es c u e  M e di c ati o n  
At t h e  dis cr eti o n  o f t h e  PI, r es c u e t h er a p y  wit h l or a z e p a m  p o/I M  0. 5-5  m g  m a y  b e i niti at e d  as  a 
st a n d ar d  of  c ar e tr e at m e nt f or  a c ut e  a git ati o n.   W h e n r es c u e  a d mi nistr ati o n  o c c urs, t h e 
m e di c ati o n, ti m e,  d os e,  a n d i n di c ati o n  m ust  b e  cl e arl y r e c or d e d  as ‘ F or  a git ati o n’ i n  C R F  a n d 
s o ur c e  d o c u m e nts. 
M e di c ati o ns f o r I ns o m ni a  
L or a z e p a m  or  ot h er  b e n z o di a z e pi n es  m a y  b e  a d mi nist er e d f or i ns o m ni a.   A d mi nistr ati o n  m a y  n ot 
o c c ur s o o n er t h a n  4  h o urs  aft er  d osi n g  of st u d y tr e at m e nt  a n d t h e i n di c ati o n (i ns o m ni a)  m ust  b e 
cl e arl y r e c or d e d i n  C R F  a n d s o ur c e  d o c u m e nts. 
1 0. 1 0. 2.   P r o hi bit e d  T h e r a pi es  
T h e f oll o wi n g  m e di c ati o ns  ar e  pr o hi bit e d  wit hi n  4  h o urs  pri or t o  B X C L 5 0 1  d osi n g: 
S e d ati v e/ h y p n oti cs,  b ar bit ur at es,  a n xi ol yti cs (i n cl u di n g  b e n z o di a z e pi n es),  a nti hist a mi n es 
( e. g.,  di p h e n h y dr a mi n e), s e d ati n g  a nti de pr ess a nts ( mirt a z a pi n e, tr a z o d o n e), tri pt a ns ( e. g. , 
s u m atri pt a n),  o pi oi ds. 
T h e f oll o wi n g  m e di c ati o ns  ar e  pr o hi bit e d fr o m  4  h o urs  pri or,  u ntil  6  h o urs  p ost- d os e,  u nl ess 
cli ni c all y i n di c at e d:  
A nti arr h yt h mi cs,  a nti bi oti cs/ a ntif u n g als/ a nti vir als,  a nti c h oli n er gi cs,  a nti c o n v uls a nts, 
a nti h y p ert e nsi v e (s p e cifi c all y  ot h er  al p h a- a dr e n er gi c  m e di c ati o ns i n cl u di n g  cl o ni di n e, 
g u a nf a ci n e,  pr a z osi n),  a n xi ol yti cs  or s e d ati v e- h y p n oti cs,  c e ntr all y  a cti n g  c al ci u m 
a nt a g o nist,  c h oli n o mi m eti cs,  mi gr ai n e-s er ot o ni n r e c e pt or  a g o nist,  o pi oi ds. 
A nti h y p ert e nsi v es  or  ot h er  m e di c ati o ns  c a n  b e  h el d  o n t h e  d a y  of t h e  d osi n g  at t h e  dis cr eti o n  of 
t h e i n v esti g at or. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 4  of  7 4  
1 1.   
S T U D Y  P R O C E D U R E S  
S u bj e cts  or t h eir  L A R  will  pr o vi d e  writt e n i nf or m e d  c o ns e nt,  a n d  ass e nt  as  a p pli c a bl e,  b ef or e 
a n y st u d y-r el at e d  pr o c e d ur es  ar e i niti at e d, i n cl u di n g t h e  c ess ati o n  of  pr o hi bit e d  c o n c o mit a nt 
t h er a p y. 
All s u bj e cts i n  all  c o h orts  will f oll o w t h e  S c h e d ul e  of  E v e nts  pr o vi d e d i n  T a bl e   3. 1. 
C o h ort  3 s u bj e cts,  w h o  will  p arti ci p at e i n t h e  1- w e e k s af et y  o bs er v ati o n  p eri o d,  will  als o f oll o w 
t h e  ass ess m e nts  pr o vi d e d i n T a bl e   3. 2. 
F or  P art  B,  t h e  3  P A N S S  S u p pl e m e nt ar y It e ms  will  b e  d o n e  at t h e ti m es t h e  P E C is  c o n d u ct e d, 
i n cl u di n g t h e  diff er e nt ti m e p oi nts t hr o u g h o ut t h e st u d y, list e d  b el o w fr o m S e cti o n  1 1. 1  t o 
S e cti o n  1 1. 7 . 
1 1. 1.   
P r e -S c r e e ni n g   
S u bj e cts  m ust  b e  pr e- s cr e e n e d, s cr e e n e d ,  a n d r a n d o mi z e d i nt o t h e st u d y  b ef or e  d osi n g.   W h e n 
p ossi bl e, s cr e e ni n g  a n d r a n d o mi z ati o n  will t a k e  pl a c e  o n t h e s a m e  d a y. 
T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d  at  Pr e- S cr e e ni n g (r ef er t o t h e  S c h e d ul e  of  E v e nts 
T a bl e  3. 1 ): 
•   O bt ai n  writt e n i nf or m e d  c o ns e nt fr o m s u bj e ct  or  L A R,  a n d  ass e nt if  a p pli c a bl e.  
S y m pt o ms,  u n d erst a n di n g  of st u d y,  a n d  a p pr o pri at e n ess  m ust  b e  d o c u m e nt e d i n s o ur c e.  
N o st u d y  pr o c e d ur es  m a y  b e  p erf or m e d  pri or t o  c o m pl eti o n  of t h e I C F  pr o c ess. 
•   R e vi e w i n cl usi o n  a n d  e x cl usi o n  crit eri a 
•   C oll e ct  d e m o gr a p hi c i nf or m ati o n  
•   R esti n g  a n d  ort h ost ati c  vit al si g ns 
•   R e c or d  m e di c al  hist or y, i n cl u di n g  pri or  a n d  c urr e nt t h er a pi es ( e. g.,  pr es cri pti o n  a n d  n o n-
pr es cri pti o n  m e di c ati o ns) 
•   P h ysi c al  e x a mi n ati o n i n cl u di n g  w ei g ht,  h ei g ht,  a n d  b o d y  m ass i n d e x 
•   1 2- l e a d  E C G  wit h r h yt h m stri p 
•   C oll e ct  bl o o d  a n d  uri n e s a m pl es f or  cli ni c al l a b or at or y t ests ( h e m at ol o g y,  cli ni c al 
c h e mistr y,  uri n al ysis,  a n d  U D S) 
•   M M S E  
•   C D R s c or e  
•   P A S  
•   P E C  
•   C- S S R S  
•   C o h ort  3  o nl y:  J o h ns  H o p ki ns  F all  Ris k  Ass ess m e nt  T o ol 
•   Ass ess  a n d r e c or d  A Es 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 5  of  7 4  
1 1. 1. 1.   
O n e -w e e k  S af et y  L e a d -i n ( C o h o rt  3  O nl y) 
Aft er  c o m pl eti o n  of t h e  Pr e- S cr e e ni n g  ass ess m e nts  a n d r e vi e w  of l a bs  a n d  E C Gs, s u bj e cts 
e nr oll e d i nt o  C o h ort  3, if  eli gi bl e ,  will  p arti ci p at e i n  a  1- w e e k s af et y  o bs er v ati o n  p eri o d.   D uri n g 
t his  1- w e e k  o bs er v ati o n  p eri o d, s u bj e cts  will  b e  ass ess e d t wi c e  d ail y f or t h eir  B P  a n d  ort h ost ati c 
B P  m e as ur e m e nts,  al o n g  wit h r e c or di n g  of i nst a n c es  of f alli n g  a n d s y n c o p e,  a n d  ass ess m e nt  o f 
A Es  a n d  c o n c o mit a nt  m e di c ati o ns.   Aft er t h e  c o n cl usi o n  of t h e  1- w e e k  o bs er v ati o n  p eri o d, 
s u bj e cts i n  C o h ort  3  will  c o m pl et e t h e s cr e e ni n g  visit  a n d f oll o w  all s u bs e q u e nt  visit s c h e d ul es  as 
o utli n e d i n  T a bl e   3. 1. 
1 1. 2.   
S c r e e ni n g  
•   R e c or d  m e di c al  hist or y, i n cl u di n g  pri or  a n d  c urr e nt t h er a pi es ( e. g.,  pr es cri pti o n  a n d  n o n-
pr es cri pti o n  m e di c ati o ns) 
•   C oll e ct  d e m o gr a p hi c i nf or m ati o n  
•   P h ysi c al  e x a mi n ati o n  
•   U TI  a n d  pr e g n a n c y  uri n e s cr e e ni n g 
•   U D S (r e q uir e d f or  C o h ort  3  o nl y) 
•   N ot e:   U D S  will  b e r e - c oll e ct e d f or  C o h orts  1  a n d  2 if  m or e t h a n  2 1  d a ys  h a v e  p ass e d 
si n c e t h e  Pr e- S cr e e ni n g  visit 
•   R esti n g  a n d  ort h ost ati c  vit al si g ns 
•   R e vi e w i n cl usi o n  a n d  e x cl usi o n  crit eri a 
•   C M AI  
•   P A S  
•   C- S S R S  
•   R e c or d  c o n c o mit a nt  m e di c ati o n  us e 
•   Ass ess  a n d r e c or d  A Es 
1 1. 3.   
P r e -D os e  
•   R e vi e w i n cl usi o n  a n d  e x cl usi o n  crit eri a 
•   R esti n g  a n d  ort h ost ati c  vit al si g ns 
•   P uls e  o xi m etr y  
•   1 2- l e a d  E C G  wit h r h yt h m stri p 
•   R a n d o mi z ati o n 
•   St u d y  dr u g  a d mi nistr ati o n 
•   C M AI  
•   P A S  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 6  of  7 4  
•   P E C  
•   A C E S  
•   C GI - S 
•   R e c or d  c o n c o mit a nt  m e di c ati o n  us e 
•   Ass ess  a n d r e c or d  A Es 
T h e  S cr e e ni n g  Visit  m a y  b e  c o n d u ct e d  o v er  m or e t h a n  o n e  d a y;  h o w e v er,  all  pr o c e d ur es  m ust  b e 
c o m pl et e d  pri or t o s u bj e ct r a n d o mi z ati o n  a n d  wit hi n  2 8  d a ys  of si g ni n g i nf or m e d  c o ns e nt. 
S cr e e n  F ail ur es:    S u bj e cts  w h o f ail i n cl usi o n  a n d/ or  e x cl usi o n  crit eri a  m a y  b e r es cr e e n e d f or t h e 
st u d y.   S u bj e cts  m a y  o nl y  b e r es cr e e n e d  o n e ti m e. 
1 1. 4.   
D a y  1,  T r e at m e nt  E v al u ati o n  
U p o n  c o m pl eti o n  of t h e  pr e-r a n d o mi z ati o n  pr o c e d ur es, t h e s u bj e ct  will  b e r a n d o mi z e d t o st u d y 
tr e at m e nt ( B X C L 5 0 1  or  pl a c e b o  S L fil m)  a n d t h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d (ref er 
t o t h e  S c h e d ul e  of  E v e nts T a bl e   3. 1 f or s p e cifi c ti m e  p oi nts): 
•   R esti n g  a n d  ort h ost ati c  vit al si g ns  
•   1 2- l e a d  E C G  wit h r h yt h m stri p 
•   P uls e  o xi m etr y  
•   C M AI  
•   P A S  
•   P E C  
•   A C E S  
•   R e c or d  c o n c o mit a nt  m e di c ati o n  us e 
•   Ass ess  a n d r e c or d  A Es 
•   Pl as m a s a m pl es f or  P K  a n al ysis.   A s a m pl e  m a y  n ot  b e  c oll e ct e d if t h e  p h ysi ci a n i n 
c h ar g e  of t h e  p ati e nt i n di c at es i n t h e s o ur c e  d o c u m e nts t h at t h e  p ati e nt is i n  a  m e nt al st at e 
t h at is  n ot  c o n d u ci v e t o  P K s a m pl e  c oll e cti o n  a n d r e c or d t h e  P E C s c or e  at t h e ti m e  of 
pr o p os e d s a m pl e  c oll e cti o n. 
•   C GI -I 
•   C GI - S 
•   B u c c al ( S L)  ass ess m e nt  
•   P K s a m pli n g  
1 1. 5.   
D a y  2 ( + 1),  F oll o w -U p  
T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d  o n  D a y  2: 
•   1 2- l e a d  E C G  wit h r h yt h m stri p 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 7  of  7 4  
•   P h ysi c al  e x a m (i n cl u di n g  w ei g ht) 
•   R esti n g  a n d  ort h ost ati c  vit al si g ns  a n d  w ei g ht  m e as ur e m e nts 
•   P uls e  o xi m etr y  
•   M M S E  
•   C D R s c or e  
•   P E C  
•   P A S  
•   C GI - S 
•   Pl as m a s a m pl e f or  P K  a n al ysis  at  2 4  h o urs  ±  1  h o ur  p ost- d osi n g 
•   C- S S R S  
•   B u c c al ( S L)  ass ess m e nt  
•   R e c or d  c o n c o mit a nt  m e di c ati o n  us e 
•   Ass ess  a n d r e c or d  A Es 
1 1. 6.   
D a y  3  
T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d  o n  D a y  3: 
•   C oll e ct  bl o o d  a n d  uri n e s a m pl es f or  cli ni c al l a b or at or y t ests ( h e m at ol o g y,  cli ni c al 
c h e mistr y,  a n d  uri n al ysis) 
•   P A S  
•   P E C  
•   R e c or d  c o n c o mit a nt  m e di c ati o n  us e 
•   Ass ess  a n d r e c or d  A Es 
1 1. 7.   
D a y  7   +  2 D a ys  
T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d  o n  D a y  7  +  2  d a ys: 
•   C oll e ct  bl o o d  a n d  uri n e s a m pl es f or  cli ni c al l a b or at or y t ests ( h e m at ol o g y,  cli ni c al 
c h e mistr y,  a n d  uri n al ysis) 
•   C M AI  
•   P A S  
•   P E C  
•   R e c or d  c o n c o mit a nt  m e di c ati o n  us e 
•   Ass ess  a n d r e c or d  A Es 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 8  of  7 4  
1 2.   
S T U D Y  A S S E S S M E N T S  
1 2. 1.   
Effi c a c y 
T h e  eff e ct  of  st u d y  dr u g  will  b e  e v al u at e d  usi n g s e v er al  v ali d at e d i nstr u m e nts  as  d es cri b e d 
b el o w. 
1 2. 1. 1.   
P A N S S -E x cit e d  C o m p o n e nt ( P E C)  
Ass ess m e nt  of  dr u g  eff e ct  o n  a c ut e  a git ati o n  will  b e  d o n e  usi n g t h e  P ositi v e  a n d  N e g ati v e 
S y n dr o m e  S c al e  –  E x cit e d  C o m p o n e nt ( P E C).   T h e  P E C  c o m pris es  5 it e ms  ass o ci at e d  wit h 
a git ati o n:  p o or i m p uls e  c o ntr ol, t e nsi o n,  h ostilit y,  u n c o o p er ati v e n ess,  a n d  e x cit e m e nt;  e a c h 
s c or e d  1 ( mi ni m u m) t o  7 ( m a xi m u m).   T h e  P E C, t h e s u m  of t h es e  5 s u bs c al es, t h us r a n g es fr o m 
5 t o  3 5. 
1 2. 1. 2.   
C o h e n  M a nsfi el d  A git ati o n I n v e nt o r y ( C M AI) 
Ass ess m e nt  of  dr u g  eff e ct  o n fr e q u e n c y  of  a c ut e  a git ati o n  will  b e  als o  d o n e  usi n g t h e  C M AI.  
T h e  C M AI is  a r ati n g  q u esti o n n air e  c o nsisti n g  of  2 9  b e h a vi ors  e a c h r at e d  o n  a  7- p oi nt s c al e  of 
fr e q u e n c y.  It is  p ossi bl e t h at  all  2 9  b e h a vi ors  will  n ot  b e r el e v a nt t o  a s p e cifi c  p ati e nt.   O nl y 
b e h a vi ors  m a nif est  b y t h e s u bj e ct  at  b as eli n e  will  b e  ass ess e d t hr o u g h o ut t h e st u d y r es ulti n g i n  a 
m o difi e d  C M AI.   B e h a vi ors  w hi c h  ar e  pr es e nt i m m e di at el y  pr e- d os e  will  b e r at e d t hr o u g h o ut t h e 
p ost- d os e ti m e p oi nts.   At  e a c h ti m e p oi nt  aft er  Pr e -d os e t h e r at er  will  n ot e t h at it e ms ( b e h a vi ors) 
w hi c h  w er e  n ot  m a nif est  pri or t o  d osi n g  h a v e  n ot  e m er g e d si n c e l ast  C M AI  ass ess m e nt.   S h o ul d 
t h e y  e m er g e, t h es e it e ms s h all  b e i n cl u d e d i n r ati n gs. 
1 2. 1. 3.   
A git ati o n- C al m n ess  E v al u ati o n  S c al e ( A C E S)  
T h e  A C E S is  a si n gl e it e m  m e as ur e r ati n g  o v er all  a git ati o n  a n d s e d ati o n,  w h er e  1 i n di c at es 
m ar k e d  a git ati o n;  2  –  m o d er at e  a git ati o n;  3  –  mil d  a git ati o n;  4  –  n or m al  b e h a vi or;  5  –  mil d 
c al m n ess;  6  –  m o d er at e  c al m n ess;  7  –  m ar k e d  c al m n ess;  8  –  d e e p sl e e p;  a n d  9  –  u n ar o us a bl e. 
1 2. 1. 4.   
Pitts b u r g  A git ati o n  S c al e ( P A S)  
T h e  Pitts b ur g  A git ati o n  S c al e ( P A S) is  a n i nstr u m e nt  b as e d  o n  dir e ct  o bs er v ati o ns  of t h e  p ati e nt 
t h at is  d e v el o p e d t o  m o nit or t h e s e v erit y  of  a gitati o n  ass o ci at e d  wit h  d e m e nti a.   T h er e  ar e 
4  b e h a vi or  gr o u ps  o bs er v e d ( usi n g  a  0 t o  4- p oi nt s c al e) i n t h e  p ati e nt,  A b err a nt  V o c ali z ati o n, 
M ot or  A git ati o n,  A g gr essi v e n ess,  R esti n g  C ar e. 
1 2. 1. 5.   
C GI -S  a n d  C GI -I 
B ot h  C GI-I  a n d  C GI- S  will  b e f o c us e d  o n t h e s e v erit y  of  a git ati o n r at h er t h a n t h e s e v erit y  of t h e 
o v er all ill n ess  of  d e m e nti a.  
Cli ni c al  Gl o b al I m pr essi o n  of  S e v erit y ( C GI - S)  will  b e r at e d  b as e d  u p o n t h e s e v erit y  of  a git ati o n 
at s cr e e ni n g  a n d  pr e- d os e (i m m e di at el y  pri or t o st art  of  d osi n g). 
S e v erit y  of  a git ati o n  will  b e  ass ess e d  b as e d  o n f oll o wi n g s c al e: 
0  =  N ot  ass ess e d  
1  =  N or m al  n ot  at  all s y m pt o m ati c  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  4 9  of  7 4  
2  =  Mi ni m all y s y m pt o m ati c - f e w  or  mil d s y m pt o ms -littl e i nt erf er e n c e  wit h  p ati e nts 
f u n cti o ni n g 
3  =  Mil dl y s y m pt o m ati c -l o w l e v el  of s y m pt o ms-littl e i nt erf er e n c e i n s o ci al f u n cti o ni n g 
4  =  M o d er at el y s y m pt o m ati c-s o m e  pr o mi n e nt s y m pt o ms-s o m e i nt erf er e n c e i n f u n cti o ni n g 
5  =  M ar k e dl y s y m pt o m ati c- si g nifi c a nt s y m pt o ms  wit h  v er y s u bst a nti al i nt erf er e n c e i n 
f u n cti o ni n g 
6  =  S e v er el y s y m pt o m ati c-  v er y  m ar k e d s y m pt o ms  m a k e it  diffi c ult f or  p ati e nts t o  e n g a g e 
wit h  ot h ers  
7  =  A m o n g t h e  m ost  e xtr e m el y s y m pt o m ati c s u bj e cts -e xtr e m e s y m pt o ms  -p ati e nt is 
i n c a p a cit at e d  or  hi g hl y  d a n g er o us t o s elf  or  ot h ers r e q uir es  e xtr a  c ar e  a n d s u p er visi o n 
Dr u g r es p o ns e  o n  a git ati o n  will  b e  e v al u at e d  b y t h e  Cli ni c al  Gl o b al I m pr essi o ns  – I m pr o v e m e nt 
( C GI-I)  w hi c h is  p erf or m e d  aft er  d osi n g  a n d  e v al u at e d r el ati v e t o  pr e- d os e  b as eli n e  a git ati o n. 
T h e  C GI -I s c or es r a n g e fr o m  1 t o  7: 
0 = n ot  ass ess e d ( missi n g), 
1 = v er y  m u c h i m pr o v e d, 
2 = m u c h i m pr o v e d, 
3 = mi ni m a ll y i m pr o v e d, 
4 = n o  c h a n g e, 
5 = mi ni m all y  w ors e,  
6 = m u c h  w ors e, 
7 = v er y  m u c h  w ors e 
1 2. 2.   
Cli ni c al  Di a g n osis  a n d  D es c ri pti o n  of  D e m e nti a   
T h e s u bt y p e  of  d e m e nti a  will  b e  d et er mi n e d  a n d r e c or d e d  b as e d  u p o n  cli ni c al  n e ur ol o gi c  a n d 
ps y c hi atri c  e v al u ati o n t o  i n cl u d e r e vi e w  of  all  a v ail a bl e  m e di c al i nf or m ati o n,  m e di c al r e c or ds, 
d o c u m e nt ati o n  of  pri or  e v al u ati o ns, f a mil y/ c ar et a k er i nt er vi e ws, r e c or ds, l a b or at or y,  g e n eti cs  or 
ot h er  bi o m ar k ers,  a n d r es ults  of  n e ur oi m a gi n g (if  a v ail a bl e). 
T h e f oll o wi n g s c al es  will  c h ar a ct eri z e s u bj e ct’s  d e m e nti a ( D S M - 5  M aj or  N e ur o c o g niti v e 
dis or d er) i n t er ms  of  c o g niti v e  a n d f u n cti o n al i m p air m e nt. 
1 2. 2. 1.   
M M S E  
T h e  F olst ei n  Mi ni- M e nt al  St at e  E x a mi n ati o n ( M M S E) is  a n  e x a m t h at t ests  a n  el d erl y  p ers o n's 
c o g niti v e  a bilit y.   D o m ai ns  m e as ur e d  b y t h e  M M S E i n cl u d e  ori e nt ati o n t o ti m e  a n d  pl a c e, 
r e gistr ati o n,  att e nti o n  a n d  c al c ul ati o n, r e c all,  n a mi n g, r e p etiti o n,  c o m pr e h e nsi o n, r e a di n g, 
writi n g,  a n d  dr a wi n g.   T h e  m a xi m u m  p oi nts  t ot al  o n t his t est is  3 0.   A n y s c or e  of  2 4  or  m or e ( o ut 
of  3 0) i n di c at es  a  n or m al  c o g niti o n.   B el o w t his, s c or es  c a n i n di c at e s e v er e ( ≤ 9  p oi nts),  m o d er at e 
( 1 0– 1 8  p oi nts)  or  mil d ( 1 9 – 2 3  p oi nts)  c o g niti v e i m p air m e nt.  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 0  of  7 4  
1 2. 2. 2.   
C D R  S c o r e  
T h e  C D R ®  ( Al z h ei m er's  Dis e as e  R es e ar c h  C e nt er,  W as hi n gt o n  U ni v ersit y,  St  L o uis) is  a  5- p oi nt 
s c al e  us e d t o  c h ar a ct eri z e si x  d o m ai ns  of  c o g niti v e  a n d f u n cti o n al  p erf or m a n c e  a p pli c a bl e t o 
Al z h ei m er  Dis e as e  a n d r el at e d  d e m e nti as:  m e m or y,  ori e nt ati o n, j u d g m e nt  &  pr o bl e m s ol vi n g, 
c o m m u nit y  aff airs,  h o m e  &  h o b bi es,  a n d  p ers o n al  c ar e.   A s c or e  of  0  c o n n ot es  n o  c o g n iti v e 
i m p air m e nt,  a n d t h e n t h e r e m ai ni n g f o ur  p oi nts  ar e f or  v ari o us st a g es  of  d e m e nti a  w h er e: 
•   C D R - 0  =  n or m al 
•   C D R - 0. 5  =  v er y  mil d  d e m e nti a 
•   C D R -1  =  mil d  
•   C D R -2  =  m o d er at e  
•   C D R -3  = s e v er e . 
1 2. 3.   
P h a r m a c o ki n eti cs  
Bl o o d s a m pl es ( 4  m L)  will  b e  c oll e ct e d  at  0. 5,  1,  2,  4,  8  a n d  2 4  h o urs  p ost- d os e,  a n d f or  P art  B 
s u bj e cts,  a n  a d diti o n al s a m pl e  will  b e  c oll e ct e d if  p ossi bl e,  b et w e e n  1 0  a n d  1 2  h o urs  p er t h e 
S c h e d ul e  of  E v e nts  T a bl e   3. 1.   T h e  8  h o ur s a m pl e  c o ul d  h a v e  a  wi n d o w  of  7- 9  h o urs  p ost  d os e 
a n d t h e  n e xt s a m pl e  c o ul d  h a v e  a  wi n d o w  of  1 0- 1 2  h o urs  p ost  d os e.  
A s a m pl e  m a y  n ot  b e  c oll e ct e d if t h e  p h ysi ci a n i n  c h ar g e  of t h e  p ati e nt i n di c at es i n t h e s o ur c e 
d o c u m e nts t h at  t h e  p ati e nt is i n  a  m e nt al st at e t h at is  n ot  c o n d u ci v e t o  P K s a m pl e  c oll e cti o n  a n d 
r e c or d t h e  P E C s c or e  at t h e ti m e  of  pr o p os e d s a m pl e  c oll e cti o n. 
F or  e a c h s u bj e ct,  u p t o  6  bl o o d s a m pl es ( 2 4  m L  of  bl o o d)  will  b e  c oll e ct e d  d uri n g t h e st u d y f or 
P K  a n al ysis.  I n  a d diti o n,  a p pr o xi m at el y  1 5  m L  of  bl o o d  will  b e  c oll e ct e d  at s cr e e ni n g, 
a p pr o xi m at el y  1 5  m L  of  bl o o d  will  b e  c oll e ct e d  at  D a y  3,  a n d  a p pr o xi m at el y  1 5  m L  of  bl o o d 
will  b e  c oll e ct e d  at  D a y  7  ( + 2  d a ys) f or  cli ni c al l a b or at or y t esti n g.   T h e t ot al  v ol u m e  of  bl o o d 
c oll e ct e d  d uri n g t h e st u d y is  e x p e ct e d t o  b e  a p pr o xi m at el y  6 9  m L. 
F or r e - d os e d s u bj e cts  o nl y:   a n  e xtr a  P K  bl o o d s a m pl e ( 4  m L)  will  b e  c oll e ct e d  at  2. 5  h o urs 
p ost- first  d os e i n  a d diti o n t o t h e  ot h er ti m es, t ot ali n g  a p pr o xi m at el y  7 3  m L.   All  P K s a m plin g 
will  o c c ur  o nl y  aft er  all  ot h er  ass ess m e nts  at t h at ti m e  p oi nt  ar e  c o n d u ct e d.  
1 2. 3. 1.   
S a m pl e  C oll e cti o n  &  P r o c essi n g  
D et ails  of t h e s a m pl e  pr o c ess  will  b e  pr o vi d e d i n  a  P K s a m pl e  m a n u al,  b ut it is  e n visi o n e d t o  b e 
t h e f oll o wi n g  pr o c ess: 
•   Bl o o d s a m pl es  will  b e  c o ll e ct e d i n  4  m L  v a c ut ai n er t u b es  c o nt ai ni n g  K2E D T A.  
•   T h e ti m e  a n d  d at e  of t h e  c oll e cti o n  of  e a c h  bl o o d s a m pl e  will  b e r e c or d e d. 
•   Aft er t h e  bl o o d s a m pl e  h as  b e e n  dr a w n i nt o t h e  v a c ut ai n er t u b e, it  will  b e  g e ntl y i n v ert e d 
at l e ast  8 ti m es,  p er mitti n g t h e  bl o o d  s p e ci m e n t o  mi x  wit h t h e  a nti c o a g ul a nt  a n d  a v oi d 
cl otti n g  of t h e s a m pl e.  
•   K e e p t h e t u b es  o n i c e  u ntil t h e  bl o o d s a m pl es  c a n  b e  c e ntrif u g e d.   C e ntrif u g e  bl o o d 
s a m pl es  at  a p pr o xi m at el y  1 5 0 0  g f or  1 5  mi n ut es  at  a p pr o xi m at el y  4 ° C. 




Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 2  of  7 4  
ass ur a n c e st at e m e nt  will  b e i n cl u d e d i n t h e fi n al  cli ni c al st u d y r e p ort ( C S R).   C o pi es  of s eri all y 
s el e ct e d sa m pl e  c hr o m at o gr a ms f or  2 0 %  of  all s a m pl es  will  b e i n cl u d e d i n t h e fi n al r e p ort. 
1 2. 4. 2.   
Bi o a n al yti c al  M et h o d ol o g y 
T h e  bi o a n al yti c al  m et h o d,  ass a y  v ali d ati o n,  a n d  bi o a n al yti c al r e p ort f or t his st u d y  will  b e 
pr o vi d e d  b y t h e  bi o a n al yti c al i n v esti g at or.   F ull  v ali d ati o n  of  a s e nsiti v e  ass a y f or t h e  a p pr o pri at e 
a n al yt e i n  bi ol o gi c al fl ui d, i n cl u di n g  pr e cisi o n,  a c c ur a c y, r e pr o d u ci bilit y,  a n d s el e cti vit y  will  b e 
i n cl u d e d i n t h e fi n al r e p ort.   T h e  bi o a n al yti c al r e p ort  will i n cl u d e t h e st a bilit y  of t h e fr o z e n 
s a m pl es, li mit  of  q u a ntit ati o n, r e c o v er y,  a n d  a s u m m ar y  of t h e st a n d ar d  c ur v es. 
1 2. 5.   
S af et y 
S af et y  will  b e  ass ess e d  d uri n g t h e st u d y  b y t h e  m o nit ori n g  a n d r e c or di n g  of  A Es,  cli ni c al 
l a b or at or y t est r es ults ( h e m at ol o g y,  bi o c h e mistr y,  a n d  uri n al ysis),  vit al si g n  m e as ur e m e nts 
(s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur es,  h e art r at e  m e as ur e d  as  p uls e, r es pir at or y r at e,  a n d 
t e m p er at ur e),  E C G,  a n d  p h ysi c al  e x a mi n ati o n fi n di n gs. 
1 2. 5. 1.   
A d v e rs e  E v e nts  
1 2. 5. 1. 1.   A d v e rs e  E v e nt  D efi niti o ns  
A n  A E is  d efi n e d  as  a n y  u nt o w ar d  m e di c al  o c c urr e n c e i n  a  s u bj e ct  or  cli ni c al i n v esti g ati o n 
p ati e nt  a d mi nist er e d  a  p h ar m a c e uti c al  pr o d u ct t h at  d o es  n ot  n e c ess aril y  h a v e  a  c a us al 
r el ati o ns hi p  wit h t h e  pr o d u ct.   A n  A E  c a n t h er ef or e  b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d si g n 
(i n cl u di n g  a  n e w,  cli ni c all y i m p ort a nt  a b n or m al l a b or at or y fi n di n g), s y m pt o m,  or  dis e as e 
t e m p or all y  ass o ci at e d  wit h t h e  pr o d u ct,  w h et h er it is r el at e d t o t h e  pr o d u ct. 
Pr e - e xisti n g  dis e as es  or  c o n diti o ns  will  n ot  b e  c o nsi d er e d  A Es  u nl ess t h er e is  a n i n cr e as e i n t h e 
fr e q u e n c y  or s e v erit y,  or  a  c h a n g e in t h e  q u alit y,  of t h e  dis e as e  or  c o n diti o n.   W ors e ni n g  of  a 
pr e e xisti n g  c o n diti o n is  c o nsi d er e d  a n  A E. 
A n  e x p e ct e d  A E is  o n e f or  w hi c h t h e  n at ur e  or s e v erit y is  c o nsist e nt  wit h t h e  k n o w n  A E  pr ofil e 
of t h e  pr o d u ct.   F or  a n i n v esti g ati o n al  dr u g, t h e  k n o w n i nf or m ati o n is  c o nt ai n e d i n t h e 
i n v esti g at or  br o c h ur e.   F or  a  m ar k et e d  dr u g, t h e  k n o w n i nf or m ati o n is i n t h e  c urr e nt  p a c k a g e 
i ns ert. 
A n  u n e x p e ct e d  A E is  o n e f or  w hi c h t h e s p e cifi cit y  or s e v erit y is  n ot  c o nsist e nt  wit h t h e  c urr e nt 
i n v esti g at or  br o c h ur e  or  p a c k a g e i ns ert.   F or  e x a m pl e,  h e p ati c  n e cr osis  w o ul d  b e  u n e x p e ct e d 
( gr e at er s e v erit y) if t h e i n v esti g at or  br o c h ur e  or  p a c k a g e i ns ert  o nl y list e d  el e v at e d  h e p ati c 
e n z y m es  or  h e p atitis.   Li k e wis e,  c er e br al t hr o m b o e m b olis m  a n d  c er e br al  v as c ulitis  w o ul d  b e 
u n e x p e ct e d ( gr e at er s p e cifi cit y) if t h e i n v esti g at or  br o c h ur e  or  p a c k a g e i ns ert  o nl y list e d  c er e br al 
v as c ul ar  a c ci d e nts.  
F urt h er m or e, r e p orts t h at  a d d si g nifi c a nt i nf or m ati o n  o n s p e cifi cit y  or s e v erit y  of  a  k n o w n, 
alr e a d y  d o c u m e nt e d  a d v ers e r e a cti o n  c o nstit ut e  u n e x p e ct e d  A Es.   E x a m pl es i n cl u d e  a c ut e r e n al 
f ail ur e  as  a n  e x p e ct e d  a d v ers e r e a cti o n  wit h  a s u bs e q u e nt  n e w  o c c urr e n c e  of i nt erstiti al  n e p hritis 
a n d  h e p atitis  wit h  a first  o c c urr e n c e  of f ul mi n at e  h e p atitis.  
A s eri o us  A E ( S A E) is  a n y  u nt o w ar d  m e di c al  o c c urr e n c e t h at  at  a n y  d os e: 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 3  of  7 4  
•   R es ults i n  d e at h  
•   Is lif e t hr e at e ni n g 
•   R e q uir es i n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n 
•   R es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y  or i n c a p a cit y  
•   Is  a  c o n g e nit al  a n o m al y 
•   Is  a n i m p ort a nt  m e di c al  e v e nt 
M e di c al  a n d s ci e ntifi c j u d g m e nt s h o ul d  b e  us e d i n  d e ci di n g  w h et h er it is  a p pr o pri at e t o  c o nsi d er 
ot h er sit u ati o ns s eri o us, s u c h  as i m p ort a nt  m e di c al  e v e nts t h at  m a y  n ot  b e i m m e di at el y lif e 
t hr e at e ni n g  or r es ult i n  d e at h  or  h os pit ali z ati o n  b ut  m a y j e o p ar di z e t h e s u bj e ct  or  m a y r e q uir e 
i nt er v e nti o n t o  pr e v e nt  a n ot h er  of t h e  o ut c o m es list e d i n t h e  d efi niti o n  pr e vi o usl y.   E x a m pl es  of 
s u c h  m e di c al  e v e nts i n cl u d e  all er gi c  br o n c h os p as m r e q uiri n g i nt e nsi v e tr e at m e nt i n  a n 
e m er g e n c y r o o m  or  at  h o m e,  bl o o d  d ys cr asi as  or  c o n v ulsi o ns t h at  d o  n ot r es ult i n i n p ati e nt 
h os pit ali z ati o n,  or t h e  d e v el o p m e nt  of  dr u g  d e p e n d e n c y  or  dr u g  a b us e. 
A n  el e cti v e  h os pit al  a d missi o n t o tr e at  a  c o n diti o n  pr es e nt  b ef or e  e x p os ur e t o t h e st u d y  dr u g  or  a 
h os pit al  a d missi o n f or  a  di a g n osti c  e v al u ati o n  of  a n  A E  d o es  n ot  q u alif y t h e  c o n diti o n  or  e v e nt  as 
a n  S A E.   A  n e wl y  di a g n os e d  pr e g n a n c y i n  a s u bj e ct  w h o  h as r e c ei v e d  a st u d y  dr u g is  n ot 
c o nsi d er e d  a n  S A E  u nl ess it is s us p e ct e d t h at t h e st u d y  dr u g i nt er a ct e d  wit h  a  c o ntr a c e pti v e 
m et h o d  a n d l e d t o t h e  pr e g n a n c y;  h o w e v er, t h e  m e di c al  m o nit or s h o ul d  b e  m a d e  a w ar e  of  a 
n e wl y  di a g n os e d  pr e g n a n c y  as s o o n  as  p ossi bl e  aft er sit e  n otifi c ati o n.   A  c o n g e nit al  a n o m al y i n 
a n i nf a nt  b or n t o  a  m ot h er  w h o  w as  e x p os e d t o t h e st u d y  dr u g  d uri n g  pr e g n a n c y is  a n  S A E. 
1 2. 5. 1. 2.   E li citi n g  a n d  D o c u m e nti n g  A d v e rs e  E v e nts 
T h e i n v esti g at or is r es p o nsi bl e f or  e ns uri n g t h at  all  A Es  a n d  S A Es  ar e r e c or d e d i n t h e  C R F  a n d 
r e p ort e d t o t h e  m e di c al  m o nit or.   A d v ers e  e v e nts  will  b e  c oll e ct e d fr o m t h e ti m e  of t h e  d os e  of 
st u d y  m e di c ati o n t hr o u g h t h e  D a y  7 ( E n d  of  St u d y)  or  E arl y  Dis c o nti n u ati o n  visit. 
At  e a c h  visit, s u bj e cts  will  b e  as k e d f or  a n y  m e di c all y r el at e d  c h a n g es i n t h eir  w ell - b ei n g.   T h e y 
will  als o  b e  as k e d if t h e y  h a v e  h a d  a n y  a c ci d e nts,  us e d  a n y  n e w  m e di c ati o ns,  or  c h a n g e d 
c o n c o mit a nt  m e di c ati o n r e gi m e ns ( b ot h  pr es cri pti o n  a n d  o v er- t h e- c o u nt er  m e di c ati o ns).  I n 
a d diti o n t o s u bj e ct  o bs er v ati o ns,  A Es  will  b e  d o c u m e nt e d fr o m  a n y  d at a  c oll e ct e d  o n t h e  A E 
p a g e  of t h e  C R F ( e. g.,  cli ni c al l a b or at or y  v al u es,  p h ysi c al  e x a mi n ati o n fi n di n gs,  a n d  E C G 
c h a n g es)  or  ot h er  d o c u m e nts t h at  ar e r el e v a nt t o s u bj e ct s af et y.  
1 2. 5. 1. 3.   R e p o rti n g  A d v e rs e  E v e nts  
All  A Es r e p ort e d  or  o bs er v e d  d uri n g t h e st u d y  will  b e r e c or d e d  o n t h e  A E  p a g e  of t h e  C R F.  
I nf or m ati o n t o  b e  c oll e ct e d i n cl u d es  dr u g tr e at m e nt, t y p e  of  e v e nt, ti m e  of  o ns et,  d os e, 
i n v esti g at or-s p e cifi e d  ass ess m e nt  of s e v erit y  a n d r el ati o ns hi p t o st u d y  dr u g, ti m e  of r es ol uti o n  of 
t h e  e v e nt, s eri o us n ess,  as  w ell  as  a n y r e q uir e d tr e at m e nt  or  e v al u ati o ns,  a n d  o ut c o m e.   A d v ers e 
e v e nts r es ulti n g fr o m  c o n c urr e nt ill n ess es, r e a cti o ns t o  c o n c urr e nt ill n ess es, r e a cti o ns t o 
c o n c urr e nt  m e di c ati o ns,  or  pr o gr essi o n  of  dis e as e st at es  m ust  als o  b e r e p ort e d.   All  A Es  will  b e 
f oll o w e d t o  a d e q u at e r es ol uti o n.   T h e l at est  v ersi o n  of t h e  M e di c al  Di cti o n ar y f or  R e g ul at or y 
A cti viti es ( M e d D R A )  will  b e  us e d t o  c o d e  all  A Es. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 4  of  7 4  
A n y  m e di c al  c o n diti o n t h at is  pr es e nt  at t h e ti m e t h at t h e s u bj e ct is s cr e e n e d  b ut  d o es  n ot 
d et eri or at e s h o ul d  n ot  b e r e p ort e d  as  a n  A E.   H o w e v er, if it  d et eri or at es  at  a n y ti m e  d uri n g t h e 
st u d y, it s h o ul d  b e r e c or d e d  as  a n  A E.  
T h e i n v esti g at or  or  d esi g n e e  m ust r e p ort  a n y  A E t h at  m e ets t h e  crit eri a f or  a n  S A E 
(S e cti o n  1 2. 5. 1. 1 ) t o t h e  m e di c al  m o nit or  wit hi n  2 4  h o urs  of first  b e c o mi n g  a w ar e  of t h e  e v e nt 
b y t el e p h o n e.   At t h e ti m e  of first  n otifi c ati o n, t h e i n v esti g at or  or  d esi g n e e s h o ul d  pr o vi d e  at  a 
mi ni m u m t h e f oll o wi n g i nf or m ati o n if  a v ail a bl e:  
•   I n v esti g at or i nf or m ati o n ( n a m e,  p h o n e, f a x,  e-m ail)  
•   Pr ot o c ol  n u m b er 
•   S u bj e ct’s st u d y i d e ntifi c ati o n  a n d i niti als  
•   S u bj e ct’s  d at e  of  birt h 
•   D at e  of  d os e  of st u d y  dr u g 
•   Ti m e  a n d  d at e  of  o c c urr e n c e  of t h e  e v e nt  
•   A  bri ef  d es cri pti o n  of t h e  e v e nt,  o ut c o m e t o  d at e,  a n d  a n y  a cti o ns t a k e n 
Wit hi n  2 4  h o urs  of t h e i niti al  n otifi c ati o n, t h e i n v esti g at or  m ust  e -m ail  a  writt e n  S A E r e p ort f or m 
t o t h e  m e di c al  m o nit or/ S af et y t e a m.   A n y  missi n g  or  a d diti o n al r el e v a nt i nf or m ati o n  a b o ut t h e 
S A E s h o ul d  b e  pr o vi d e d i n  a  writt e n f oll o w- u p  S A E r e p ort f or m.   T h e i n v esti g at or s h o ul d  als o 
e ns ur e t h at  a n y  a d diti o n al i nf or m ati o n r e q u est e d  a b o ut t h e  e v e nt ( e. g.,  h os pit al r e p orts,  a ut o ps y 
r e p orts) is  pr o vi d e d  as s o o n  as it is  a v ail a bl e. 
T h e i n v esti g at or is r e q uir e d t o  c o m pl y  wit h  a p pli c a bl e r e g ul ati o ns (i n cl u di n g l o c al l a ws  a n d 
g ui d a n c e) r e g ar d i n g t h e  n otifi c ati o n  of t h e i nstit uti o n al r e vi e w  b o ar d (I R B). 
T h e f oll o wi n g  c o nt a ct i nf or m ati o n is t o  b e  us e d f or  S A E r e p orti n g: 
Bi o X c el  T h e r a p e uti cs, I n c.  S A E  m ail b o x:  
 
1 2. 5. 1. 3. 1.  Ass ess m e nt  of  S e v e rit y  
T h e s e v erit y  or i nt e nsit y  of  a n  A E r ef ers t o t h e  e xt e nt t o  w hi c h it  aff e cts t h e s u bj e ct’s  d ail y 
a cti viti es.   S e v erit y  will  b e r at e d  as  mil d,  m o d er at e,  or s e v er e  usi n g t h e f oll o wi n g  crit eri a:  
Mil d:   
Is  us u all y tr a nsi e nt  a n d  m a y r e q uir e  o nl y  mi ni m al tr e at m e nt  or 
t h er a p e uti c i nt er v e nti o n.   T h e  e v e nt  d o es  n ot  g e n er all y i nt erf er e 
wit h  us u al  a cti viti es  of  d ail y li vi n g.  
M o d er at e:   
Is  us u all y  all e vi at e d  wit h  a d diti o n al s p e cifi c t h er a p e uti c 
i nt er v e nti o n.   T h e  e v e nt i nt erf er es  wit h  us u al  a cti viti es  of  d ail y 
li vi n g,  c a usi n g  dis c o mf ort  b ut  p os es  n o si g nifi c a nt  or  p er m a n e nt 
ris k  of  h ar m t o t h e s u bj e ct. 
S e v er e:  
I nt err u pts  us u al  a cti viti es  of  d ail y li vi n g, si g nifi c a ntl y  aff e cts 
cli ni c al st at us,  or  m a y r e q uir e i nt e nsi v e t h er a p e uti c i nt er v e nti o n  
P P D


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 5  of  7 4  
C h a n g es i n t h e s e v erit y  of  a n  A E s h o ul d  b e  d o c u m e nt e d t o  all o w  ass ess m e nt  of t h e  d ur ati o n  of 
t h e  e v e nt  at  e a c h l e v el  of i nt e nsit y t o  b e  p erf or m e d.   S eri o us  A Es  c h ar a ct eri z e d  as i nt er mitt e nt 
r e q uir e  d o c u m e nt ati o n  of  o ns et  a n d  d ur ati o n  of  e a c h  e pis o d e. 
1 2. 5. 1. 3. 2.  Ass ess m e nt  of  R el ati o ns hi p  
T h e i n v esti g at or’s  ass ess m e nt  of  a n  A E’s r el ati o ns hi p t o st u d y  dr u g is  p art  of t h e  d o c u m e nt ati o n 
pr o c ess  b ut is  n ot  a f a ct or i n  d et er mi ni n g  w h at is  or is  n ot r e p ort e d i n t h e st u d y.  If t h er e is  a n y 
d o u bt  as t o  w h et h er  a  cli ni c al  o bs er v ati o n is  a n  A E, t h e  e v e nt s h o ul d  b e r e p o rt e d. 
T h e r el ati o ns hi p  or  ass o ci ati o n  of t h e st u d y  dr u g i n  c a usi n g  or  c o ntri b uti n g t o t h e  A E  will  b e 
c h ar a ct eri z e d  usi n g t h e f oll o wi n g  cl assifi c ati o n  a n d  crit eri a:  
N ot r el at e d:   
A n  A E  wit h  e n o u g h  e vi d e n c e t o  a c c e pt t h at t h er e is  n o  c a us al 
r el ati o ns hi p t o  a d mi nistr ati o n  of st u d y  dr u g ( e. g.,  n o t e m p or al 
r el ati o ns hi p  b e c a us e t h e st u d y  dr u g  w as  a d mi nist er e d  aft er t h e 
o ns et  of t h e  e v e nt,  a n i n v esti g ati o n s h o ws t h at st u d y  dr u g  w as 
n ot  a d mi nist er e d,  a n ot h er  c a us e  w as  pr o v e n.) 
U nli k el y/ R e m ot el y 
r el at e d: 
A n  A E, i n cl u di n g  a  cli ni c al l a b or at or y t est  a b n or m alit y,  wit h  a 
t e m p or al r el ati o ns hi p t o  a d mi nistr ati o n  of st u d y  dr u g t h at  m a k es 
a  c a us al r el ati o ns hi p i m pr o b a bl e  a n d i n  w hi c h  ot h er  dr u gs, 
e v e nts,  or  u n d erl yi n g  dis e as e  pr o vi d e  pl a usi bl e  e x pl a n ati o ns. 
P ossi bl y  r el at e d:  
A n  A E  wit h  a r e as o n a bl e ti m e s e q u e n c e t o  a d mi nistr ati o n  of 
st u d y  dr u g  b ut t h at  c o ul d  als o  b e  e x pl ai n e d  b y  c o n c urr e nt 
dis e as e  or  ot h er  dr u gs  or  e v e nts.  I nf or m ati o n  o n  dr u g 
wit h dr a w al  m a y  b e l a c ki n g  or  u n cl e ar. 
Pr o b a bl y r el at e d:  
A n  A E  wit h  a r e as o n a bl e ti m e t e m p or al s e q u e n c e fr o m 
a d mi nistr ati o n  of t h e st u d y  dr u g;  or t h e  A E f oll o ws  a  k n o w n 
p att er n  of  or r es p o ns e t o t h e st u d y  dr u g;  or  a n  alt er n ati v e 
e x pl a n ati o n ( e. g.,  c o n c o mit a nt  dis e as e,  e n vir o n m e nt f a ct ors, 
a n d/ or  c o n c o mit a nt  m e di c ati o ns) is l ess li k el y t h a n  attri b uti o n t o 
t h e st u d y  dr u g;  or t h e  A E  di mi nis h es  or  dis a p p e ars  u p o n 
c ess ati o n  of st u d y  dr u g.  
D efi nit el y  R el at e d:  A n  A E  o c c urri n g i n  a  pl a usi bl e ti m e r el ati o ns hi p t o 
a d mi nistr ati o n  of st u d y  dr u g  a n d t h at  c a n n ot  b e  e x pl ai n e d  b y  a 
c o n c urr e nt  dis e as e  or  ot h er  dr u gs  or  e v e nts.   T h e r es p o ns e t o 
wit h dr a w al  of t h e  dr u g ( d e c h all e n g e) is  cli ni c all y r e as o n a bl e.  
1 2. 5. 1. 3. 3.  D efi niti o n  of  A d v e rs e  E v e nt  O ut c o m e  at t h e  Ti m e  of  L ast  O bs e r v ati o n  
T h e  A E  o ut c o m e  at t h e ti m e  of l ast  o bs er v ati o n  will  b e  cl assif i e d  as  “r es ol v e d ”,  “r es ol v e d  wit h 
s e q u el a e ”,  “ o n g oi n g ”, “ d e at h ” , “ ot h er ” ,  or  “ u n k n o w n ”. 
“ D e at h ” s h o ul d  o nl y  b e s el e ct e d  as  a n  o ut c o m e  w h e n t h e  A E r es ult e d i n  d e at h.  If  m or e t h a n 
1  A E is  p ossi bl y r el at e d t o t h e s u bj e ct’s  d e at h, t h e  o ut c o m e  of  d e at h s h o ul d  b e i n di c at e d f or  e a c h 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 6  of  7 4  
s u c h  A E.   Alt h o u g h  “ d e at h ” is  us u all y  a n  e v e nt  o ut c o m e,  e v e nts s u c h  as s u d d e n  d e at h  or 
u n e x pl ai n e d  d e at h s h o ul d  b e r e p ort e d  as  S A Es. 
1 2. 5. 1. 4.   F oll o w- u p  of  A d v e rs e  E v e nts  
A n y  A E  will  b e f oll o w e d ( u p t o  a  m a xi m u m  of  3 0  d a ys  aft er  d osi n g  wit h st u d y  dr u g) t o  a 
s atisf a ct or y r es ol uti o n  or  u ntil t h e i n v esti g at or  d e e ms t h e  e v e nt t o  b e  c hr o ni c  or  n ot  cli ni c all y 
si g nifi c a nt  or t h e s u bj e ct t o  b e st a bl e.   All fi n di n gs r el e v a nt t o t h e fi n al  o ut c o m e  of  a n  A E  m ust 
b e r e p ort e d i n t h e s u bj e ct’s  m e di c al r e c or d  a n d r e c or d e d  o n t h e  a p pr o pri at e  C R F. 
1 2. 5. 2.   
J o h ns  H o p ki ns  F all  Ris k  Ass ess m e nt  T o ol  
T h e J o h ns  H o p ki ns  F all  Ris k  Ass ess m e nt  T o ol is  a  v ali d at e d ris k str atifi c ati o n t o ol t o f a cilit at e 
e arl y  d et e cti o n  of ris k  of f alli n g i n  a d ult i n p ati e nts  b y  ass essi n g  v ari o us  p oi nt- b as e d  crit eri a t o 
d eri v e  a t ot al ris k s c or e.  
1 2. 5. 3.   
C- S S R S  
T h e  C ol u m bi a  S ui ci d e  S e v erit y  R ati n g  S c al e ( C - S S R S) ( O q u e n d o,  2 0 0 3) is  a s ui ci d al i d e ati o n 
r ati n g s c al e.   T h e s c al e i d e ntifi es  b e h a vi ors  a n d t h o u g hts t h at  ar e  ass o ci at e d  wit h  a n i n cr e as e d 
ris k  of s ui ci d al  a cti o ns i n t h e f ut ur e.   T h e  C- S S R S  B as eli n e/ S cr e e ni n g  v ersi o n  will  b e  c o n d u ct e d 
at  Pr e - S cr e e ni n g.   T h e  C- S S R S  Si n c e  L ast  Visit  v ersi o n  will  b e  c o n d u ct e d  at  S cr e e ni n g  a n d 
2 4  h o urs  p ost- d osi n g. 
1 2. 5. 4.   
L a b o r at o r y  S af et y  Ass ess m e nts  
S a m pl es f or t h e f oll o wi n g l a b or at or y t ests  will  b e  c oll e ct e d  at t h e ti m e  p oi nts s p e cifi e d i n t h e 
S c h e d ul e  of  E v e nts  T a bl e   3. 1. 
H e m at ol o g y: 
C o nsists  of  c o m pl et e  bl o o d  c o u nt ( h e m o gl o bi n,  h e m at o crit, 
w hit e  bl o o d  c ell  c o u nt  wit h  diff er e nti al, r e d  bl o o d  c ell 
c o u nt,  a n d  pl at el et  c o u nt) 
S er u m  c h e mistr y:  
I n cl u d es  bl o o d  ur e a  nitr o g e n,  cr e ati ni n e, t ot al  bilir u bi n, 
al k ali n e  p h os p h at as e,  as p art at e  a mi n otr a nsf er as e (s er u m 
gl ut a mi c -o x al o a c eti c  tr a ns a mi n as e),  al a ni n e 
a mi n otr a nsf er as e (s er u m  gl ut a mi c  p yr u vi c tr a ns a mi n as e), 
gl u c os e,  al b u mi n,  a n d t ot al  pr ot ei n 
Uri n al ysis:  
I n cl u d es  p H, s p e cifi c  gr a vit y,  pr ot ei n,  gl u c os e,  k et o n es, 
bilir u bi n,  bl o o d,  nitrit es, l e u k o c yt es,  ur o bili n o g e n, 
mi cr os c o pi c  uri n e  a n al ysis if  di psti c k  p ositi v e 
Uri n e  pr e g n a n c y t est:   C o n d u ct e d  b y l o c al l a bs 
Uri n e  dr u g s cr e e n:  
C o c ai n e,  a m p h et a mi n e,  p h e n c y cli di n e,  b e n z o di a z e pi n es, 
m arij u a n a. ( N ot e;  m arij u a n a  p ositi v e is  all o w e d  pr o vi d e d 
s u bj e ct is  n ot  m o d er at el y t o s e v er el y  d e p e n d e nt, 
b e n z o di a z e pi n e  p ositi v e  ar e  all o w e d if  pr es cri b e d)  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 7  of  7 4  
1 2. 5. 5.   
Vit al  Si g ns  
R esti n g  vit al si g ns, i n cl u di n g s yst oli c,  di ast oli c  bl o o d  pr ess ur e  a n d  h e art r at e ( m e as ur e d  as  p uls e) 
will  b e  m e as ur e d  aft er t h e s u bj e ct  h as  b e e n i n  a r e c u m b e nt  p ositi o n f or  at l e ast  5  mi n u t es  at t h e 
ti m e  p oi nts s p e cifi e d i n t h e s c h e d ul e  of  e v e nts.   M e as ur e m e nts s h o ul d  b e  m a d e  at l e ast  1  mi n ut e 
a p art  usi n g t h e s a m e  ar m  at  e a c h  visit.  
At i n di c at e d ti m e p oi nts  ort h ost ati c  m e as ur e m e nt  of s yst oli c,  di ast oli c  bl o o d  pr ess ur e  a n d  h e art 
r at e  will  b e m e as ur e d  aft er t h e s u bj e ct  h as  b e e n st a n di n g f or  a t ot al  of  5  mi n ut es.   T e m p er at ur e 
a n d r es pir at or y r at e  will  b e r e c or d e d  w h e n  ort h ost ati c  m e as ur e m e nt is i n di c at e d i n t h e s c h e d ul e 
of  e v e nts  a n d  ar e  n ot r e q uir e d t o  b e  m e as ur e d  at r esti n g  vit al si g n ti m e p oi n ts. 
If t h e first  m e as ur e m e nt  of  vit al si g ns ( S B P,  D B P  a n d  p uls e) s h o ws t h e f oll o wi n g,  vit al si g ns  will 
b e  m e as ur e d  a g ai n i n tri pli c at e  (s a m e  ar m, s e p ar at e d  b y  at l e ast  1  mi n ut e) f or: 
•   S yst oli c  Bl o o d  Pr ess ur e  < 9 0  m m H g 
•   Di ast oli c  Bl o o d  Pr ess ur e  < 6 0  m m H g 
•   P uls e  < 6 0  b p m 
1 2. 5. 6.   
El e ct r o c a r di o g r a m  
A  1 2 -l e a d  E C G  wit h r h yt h m stri p  will  b e  p erf or m e d  at  Pr e- S cr e e ni n g,  Pr e- d os e,  a n d at  2  h o urs 
a n d  2 4  h o urs  p ost- d os e. 
1 2. 5. 7.   
P h ysi c al  E x a mi n ati o n 
A st a n d ar d  p h ysi c al  e x a mi n ati o n  will  b e  p erf or m e d  at  Pr e- S cr e e ni n g,  S cr e e ni n g,  a n d  2 4  h o ur s 
p ost- d os e.   T h e  e x a mi n ati o n  will i n cl u d e  ass ess m e nt  of s ki n,  h e a d,  e ars,  e y es,  n os e, t hr o at,  n e c k, 
t h yr oi d, l u n gs,  h e art,  c ar di o v as c ul ar,  a b d o m e n, l y m p h  n o d es,  a n d  m us c ul os k el et al 
s yst e m/ e xtr e miti es.  I nt eri m  p h ysi c al  e x a mi n ati o ns  will  b e  p erf or m e d  at t h e i n v esti g at or’s 
dis cr eti o n if  n e c ess ar y, t o  e v al u at e  A Es  or  cli ni c al l a b or at or y  a b n or m aliti es.  
H ei g ht  a n d  w ei g ht  will  b e  m e as ur e d  at  Pr e -S cr e e ni n g  a n d  w ei g ht  will  b e  m e as ur e d  a g ai n  at 
D a y   2. 
1 2. 5. 8.   
C o n c o mit a nt  M e di c ati o ns 
C o n c o mit a nt  m e di c ati o ns  will  b e  r e vi e w e d  a n d  d o c u m e nt e d  e a c h  d a y  d uri n g t h e st u d y. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 8  of  7 4  
1 3.   
S T A TI S TI C A L  M E T H O D S  
1 3. 1.   
G e n e r al  C o nsi d e r ati o ns  
A st atisti c al  a n al ysis  pl a n ( S A P) t h at  d es cri b es t h e  d et ails  of t h e  a n al ys es t o  b e  c o n d u ct e d  will  b e 
fi n ali z e d  b ef or e  d at a b as e l o c k.  I n  a d diti o n, P art  B  of t his  st u d y  will  b e  a n al y z e d s e p ar at el y  a n d  a 
s e p ar at e  S A P f or P art  B  of t his st u d y  will  b e  pr e p ar e d  a n d fi n ali z e  pri or t o  d at a b as e l o c k  of 
P art  B.  
1 3. 2.   
A n al ysis  P o p ul ati o ns  
T h e f oll o wi n g  a n al ysis  p o p ul ati o ns  ar e  pl a n n e d: 
•   S af et y  P o p ul ati o n:   All s u bj e cts  w h o r e c ei v e  st u d y  dr u g. 
•   I nt e nt t o tr e at (I T T)  P o p ul ati o n:   All s u bj e cts i n t h e  S af et y  P o p ul ati o n  w h o  h a v e  a  P E C 
S c or e.  
•   P er  Pr ot o c ol ( P P)  P o p ul ati o n:   All s u bj e cts i n t h e I T T  P o p ul ati o n  wit h  n o  m aj or  pr ot o c ol 
d e vi ati o ns. 
1 3. 3.   
St atisti c al  A n al ys es  
C o nti n u o us  v ari a bl es  will  b e s u m m ari z e d  b y tr e at m e nt  usi n g  d es cri pti v e st atisti cs ( n,  m e a n, 
m e di a n, st a n d ar d  d e vi ati o n,  mi ni m u m,  a n d  m a xi m u m).   F or  c at e g ori c al  v ari a bl es, fr e q u e n ci es 
a n d  p er c e nt a g es  will  b e  pr es e nt e d  b y tr e at m e nt.   B as eli n e is  d efi n e d  as t h e l ast  o bs er v ati o n  pri or 
t o i niti ati o n  of st u d y  m e di c ati o n.   Missi n g  d at a is  n ot  a nti ci p at e d  at t h e 2  h o ur  pri m ar y ti m e 
p oi nt.   D et ails  of t h e st atisti c al  a n al ys es  will  b e  pr o vi d e d i n t h e  S A P,  w hi c h  will  b e fi n ali z e d 
pri or t o  d at a b as e l o c k. 
1 3. 3. 1.   
S u bj e ct  Dis p ositi o n  a n d  D e m o g r a p hi c  C h a r a ct e risti cs  
S u bj e ct  dis p ositi o n  will i n cl u d e t h e  n u m b er  of s u bj e cts  w h o  e nr oll i n t h e st u d y  a n d t h e  n u m b er 
a n d  p er c e nt a g e  of s u bj e cts i n cl u d e d i n  e a c h  a n al ysis  p o p ul ati o n  b y tr e at m e nt.   T h e fr e q u e n c y  a n d 
p er c e nt a g e  of s u bj e cts  w h o  wit h dr a w  or  dis c o nti n u e fr o m t h e st u d y,  al o n g  wit h t h e r e as o n f or 
wit h dr a w al  or  dis c o nti n u ati o n,  will  b e s u m m ari z e d  b y tr e at m e nt.  
D e m o gr a p hi cs  a n d  b as eli n e  c h ar a ct eristi cs, i n cl u di n g  a g e, s e x, r a c e,  w ei g ht,  h ei g ht,  a n d  b o d y 
m ass i n d e x ( B MI),  will  b e s u m m ari z e d  b y tr e at m e nt f or t h e  S af et y  P o p ul ati o n. 
1 3. 3. 2.   
Effi c a c y  A n al ys es 
T h e  I T T  p o p ul ati o n  will  b e  a n al y z e d  a n d  c o nsist  of  all  p ati e nts  w h o t a k e  a n y st u d y  m e di c ati o n 
a n d  w h o  h a d  b ot h  b as eli n e  a n d  at l e ast  1  effi c a c y  ass ess m e nt  aft er  d osi n g.   O bs er v ati o ns 
r e c or d e d  aft er  us e  of r es c u e  m e di c ati o n  will  b e  c e ns or e d ( c o nsi d er e d  missi n g). 
T h e  pri m ar y  effi c a c y  e n d p oi nt f or t his st u d y is t h e  P E C t ot al s c or e  wit h  a  pri m ar y ti m e  p oi nt  of 
2  h o urs,  w hi c h f or  P art  B  will  b e t est e d  v ers us  pl a c e b o  usi n g  a  Mi x e d  M o d el  R e p e at e d  M e as ur es 
a p pr o a c h  wit h  al p h a  c o ntr oll e d  at t h e  0. 0 5 l e v el. 
P E C t ot al s c or es  at  e arli er ti m e  p oi nts  will  b e t est e d  hi er ar c hi c all y t o  d et er mi n e  e arli est  o ns et  of 
a cti o n,  c o n diti o n al  u p o n t h e si g nifi c a n c e  of  diff er e n c es  b et w e e n  4 0  µ g  a n d  pl a c e b o  at  2  h o urs.  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  5 9  of  7 4  
Irr es p e cti v e,  n o mi n al si g nifi c a n c e l e v els  will  b e r e p ort e d.   A d diti o n al  d et ails  will  b e  pr o vi d e d i n 
t h e P art  B  S A P.  
1 3. 3. 3.   
S af et y  A n al ys es 
All s af et y  a n al ys es  will  b e  p erf or m e d  usi n g t h e  S af et y  P o p ul ati o n.   All s u bj e cts  w h o r e c ei v e d  at 
l e ast 1  d os e  of st u d y  dr u g  will  b e i n cl u d e d i n t h e  p o p ul ati o n f or s af et y  a n al ysis. 
A d v ers e  e v e nts  will   b e  c h ar a ct eri z e d  b y t y p e, s e v erit y, s eri o us n ess,  a n d r el ati o ns hi p t o tr e at m e nt.  
A d v ers e  e v e nts  will  b e  c o d e d  b y  pr ef err e d t er m  a n d s yst e m  or g a n  cl ass  usi n g t h e l at est  v ersi o n  of 
M e d D R A.   I n ci d e n c e  of  A Es  will  b e s u m m ari z e d  b y tr e at m e nt  o v er all,  b y s e v erit y,  a n d  b y 
r el ati o ns hi p t o st u d y  dr u g.   S eri o us  A Es  a n d  A Es l e a di n g t o  dis c o nti n u ati o n  of st u d y  dr u g  will 
als o  b e  pr es e nt e d.  
Vit al si g ns,  E C G  wit h r h yt h m stri p,  a n d  cli ni c al l a b or at or y r es ults  will  b e s u m m ari z e d  b y 
tr e at m e nt.   P h ysi c al  e x a mi n ati o n fi n di n gs will  b e list e d.  
1 3. 3. 4.   
P h a r m a c o ki n eti c  A n al ys es  
A s e p ar at e  S A P f or  P K  a n al ys es  will  b e  pr e p ar e d f or t h e st u d y  a n d  will  b e fi n ali z e d  pri or t o 
d at a b as e l o c k.    D at a fr o m s u bj e cts  w h o  p arti ci p at e d i n t h e st u d y  will  b e i n cl u d e d i n t h e P K  
a n al ysis.   S u bj e cts  wit h  missi n g s a m pl e  c o n c e ntr ati o ns  will  b e i n cl u d e d i n t h e  P K  a n al ys es 
pr o vi d e d t h eir  P K  p ar a m et ers  c a n  b e  a d e q u at el y  c h ar a ct eri z e d  b as e d  u p o n t h e r e m ai ni n g  d at a.  
D e vi ati o n fr o m  pr o c e d ur es  d es cri b e d i n t his  pr ot o c ol t h at i m p a ct t h e  q u alit y  of  d at a r e q uir e d t o 
m e et t h e  o bj e cti v es  of t h e st u d y  will  b e  d o c u m e nt e d  a n d  m a y r es ult i n  e x cl usi o n  of  P K  d at a fr o m 
t h e  a n al ys es f or  a s u bj e ct.   T his i n cl u d es  a n y  d e vi ati o ns  or  e v e nts t h at  w o ul d i n v ali d at e t h e 
e v al u ati o n  of t h e  P K .   E x a m pl es  of  d e vi ati o ns  a n d  e v e nts  w hi c h  c o ul d r es ult i n  e x cl usi o n  of P K  
d at a fr o m t h e  a n al ys es i n cl u d e  e m esis  aft er  d osi n g ( wit hi n t h e  pr e d et er mi n e d ti m e), s a m pl e 
pr o c essi n g,  or  ass a y  err ors t h at l e a d t o i n a c c ur at e  bi o a n al yti c al r es ults.    Ot h er  d e vi ati o ns  or 
e v e nts,  w hi c h  d o  n ot  dis q u alif y  d at a fr o m  a n al ys es,  m a y r e q uir e  mi n or  a dj ust m e nts t o 
c al c ul ati o ns.   If t h es e  o c c ur,  d at a  a n al ys es  will  b e  a dj ust e d  a n d  d o c u m e nt e d  a c c or di n gl y s u c h t h at 
c o n cl usi o ns  ar e  n ot  bi as e d.   A n  e x a m pl e  of s u c h  a n  e v e nt i n cl u d es,  b ut is  n ot li mit e d t o,  mi n or 
d e vi ati o ns  b et w e e n t h e  a ct u al  a n d s c h e d ul e d ti m e  of s a m pl e  c oll e cti o n.  
All  P K  p ar a m et ers  will  b e  c al c ul at e d  usi n g  n o n - c o m p art m e nt al  a n al ysis  usi n g  Wi n N o nli n.  
A ct u al s a m pli n g ti m es  will  b e  us e d i n  all  P K  a n al ys es.   P er  pr ot o c ol ti m es  will  b e  us e d t o 
c al c ul at e   m e a n  pl as m a  c o n c e ntr ati o ns f or  gr a p hi c al  dis pl a ys. 
Ot h er  P K  a n al ys es  m a y  b e  p erf or m e d  as  a p pr o pri at e . 
1 3. 3. 5.   
I nt e ri m  A n al ys es  
D u e t o  a n  u n a nti ci p at e d  d el a y i n  e nr oll m e nt  a n d st u d y  p a us e  ass o ci at e d  wit h t h e  C O VI D- 1 9 
p a n d e mi c,  as  w ell  as t h e  el d erl y fr ail  p o p ul ati o n,  w e  ar e  pl a n ni n g t o  c o n d u ct  1  or  m or e  u n bli n d e d 
a n al ys es t o  e v al u at e t h e s af et y  d at a ( es p e ci all y  c ar di o v as c ul ar  e n d p oi nts) t o  h el p  g ui d e  d osi n g.  
I n  a d diti o n,  w e  h o p e t o  g ai n f urt h er  e x p eri e n c e  wit h r e g ar d t o t h e  e n d p oi nts  u n d er  c o nsi d er ati o n, 
as  m a n y  o f t h e t o ols  e m pl o y e d i n t his st u d y  ar e  y et t o  b e  c h ar a ct eri z e d i n  a s h ort e n e d st u d y  of 
t his  n at ur e. 
I nt eri m  a n al ys es  ar e  n ot  a nti ci p at e d f or P art  B  of t his st u d y. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 0  of  7 4  
1 3. 4.   
S a m pl e  Si z e  D et e r mi n ati o n  
 
 
 
 
 
 
 
C CI
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 1  of  7 4  
1 4.   
 S T U D Y  C O N D U C T  
St e ps t o  e ns ur e t h e  a c c ur a c y  a n d r eli a bilit y  of  d at a i n cl u d e t h e s el e cti o n  of  q u alifi e d i n v esti g at ors 
a n d  a p pr o pri at e st u d y sit es, r e vi e w  of  pr ot o c ol  pr o c e d ur es  wit h t h e  i n v esti g at or  a n d  ass o ci at e d 
p ers o n n el  pri or t o t h e st u d y,  p eri o di c  m o nit ori n g  visits,  a n d stri ct  d at a  m a n a g e m e nt  pr o c e d ur es. 
1 4. 1.   
S p o ns o r  a n d I n v esti g at o r  R es p o nsi biliti es  
1 4. 1. 1.   
S p o ns o r  R es p o nsi biliti es  
T h e s p o ns or is  o bli g at e d t o  c o n d u ct t h e st u d y i n  a c c or d a n c e  wit h stri ct  et hi c al  pri n ci pl es.   T h e 
s p o ns or r es er v es t h e ri g ht t o  wit h dr a w  a s u bj e ct fr o m t h e st u d y, t o t er mi n at e  p arti ci p ati o n  of  a 
st u d y sit e  at  a n y ti m e,  or t o  dis c o nti n u e t h e st u d y. 
T h e s p o ns or  a gr e es t o  pr o vi d e t h e i n v esti g at or  wit h  e n o u g h  m at eri al  a n d s u p p ort t o  p er mit t h e 
i n v esti g at or t o  c o n d u ct t h e st u d y  a c c or di n g t o t h e st u d y  pr ot o c ol. 
1 4. 1. 2.   
I n v esti g at o r  R es p o nsi biliti es  
B y si g ni n g t h e I n v esti g at or’s  A gr e e m e nt, t h e i n v esti g at or i n di c at es t h at  h e  or s h e  h as  c ar ef ull y 
r e a d t h e  pr ot o c ol, f ull y  u n d erst a n ds t h e r e q uir e m e nts,  a n d  a gr e es t o  c o n d u ct t h e st u d y i n 
a c c or d a n c e  wit h t h e  pr o c e d ur es  a n d r e q uir e m e nts  d es cri b e d i n t his  pr ot o c ol. 
T h e i n v esti g at or  als o  a gr e es t o  c o n d u ct t his st u d y i n  a c c or d a n c e  wit h  all l a ws, r e g ul ati o ns,  a n d 
g ui d eli n es  of t h e  p erti n e nt r e g ul at or y  a ut h oriti es, i n cl u di n g  a n d i n  a c c or d a n c e  wit h t h e  A pril 
1 9 9 6 I nt er n ati o n al  C o u n cil f or  H ar m o nis ati o n (I C H)  G ui d a n c e f or I n d ustr y  E 6  G o o d  Cli ni c al 
Pr a cti c e ( G C P)  a n d i n  a gr e e m e nt  wit h t h e  1 9 9 6   V ersi o n  of t h e  D e cl ar ati o n  of  H elsi n ki.   W hil e 
d el e g ati o n  of  c ert ai n  as p e cts  of t h e st u d y t o s u b-i n v esti g at ors  a n d st u d y  c o or di n at ors is 
a p pr o pri at e, t h e i n v esti g at or  will r e m ai n  p ers o n all y  a c c o u nt a bl e f or  cl os el y  o v ers e ei n g t h e st u d y 
a n d f or  e ns uri n g  c o m pli a n c e  wit h t h e  pr ot o c ol  a n d  all  a p pli c a bl e r e g ul ati o ns  a n d  g ui d eli n es.   T h e 
i n v esti g at or is r es p o nsi bl e f or  m ai nt ai ni n g  a list  of  all  p ers o ns t h at  h a v e  b e e n  d el e g at e d st u d y-
r el at e d r es p o nsi biliti es ( e. g., s u b-i n v esti g at ors  a n d st u d y  c o or di n at ors)  a n d  his  or  h er s p e cifi c 
st u d y-r el at e d  d uti es. 
I n v esti g at ors s h o ul d  e ns ur e t h at  all  p ers o ns  w h o  h a v e  b e e n  d el e g at e d st u d y-r el at e d 
r es p o nsi biliti es  ar e  a d e q u at el y  q u alifi e d  a n d i nf or m e d  a b o ut t h e  pr ot o c ol, st u d y  dr u gs,  a n d t h eir 
s p e cifi c  d uti es  wit hi n t h e  c o nt e xt  of t h e st u d y.  I n v esti g at ors  ar e r es p o nsi bl e f or  pr o vi di n g t h e 
s p o ns or  wit h  d o c u m e nt ati o n  of t h e  q u alifi c ati o ns,  G C P tr ai ni n g,  a n d r es e ar c h  e x p eri e n c e f or 
t h e ms el v es  a n d t h eir st aff  as re q uir e d  b y t h e s p o ns or  a n d t h e r el e v a nt  g o v er ni n g  a ut h oriti es. 
T o  e ns ur e  c o m pli a n c e  wit h t h e  g ui d eli n es, t h e st u d y  will  b e  a u dit e d  b y  a n i n d e p e n d e nt  p ers o n.  
T h e i n v esti g at or  a gr e es,  b y  writt e n  c o ns e nt t o t his  pr ot o c ol, t o  c o o p er at e f ull y  wit h  c o m pli a n c e 
c h e c ks  b y  all o wi n g  a c c ess t o  all st u d y  d o c u m e nt ati o n  b y  a ut h ori z e d i n di vi d u als. 
1 4. 2.   
Sit e I niti ati o n  
St u d y  p ers o n n el  m a y  n ot s cr e e n  or  e nr oll s u bj e cts i nt o t h e st u d y  u ntil  aft er r e c ei vi n g  n otifi c ati o n 
fr o m t h e s p o ns or  or its  d esi g n e e t h at t h e st u d y  c a n  b e i niti at e d  at t h e st u d y sit e.   T h e st u d y sit e 
will  n ot  b e  a ut h ori z e d f or st u d y i niti ati o n  u ntil: 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 2  of  7 4  
1.   T h e st u d y sit e  h as r e c ei v e d t h e  a p pr o pri at e I R B  a p pr o v al f or t h e  pr ot o c ol  a n d t h e 
a p pr o pri at e i nf or m e d  c o ns e nt. 
2.   All  G C P  d o c u m e nts  h a v e  b e e n s u b mitt e d t o  a n d  a p pr o v e d  b y t h e s p o ns or  or its  d esi g n e e. 
3.   T h e st u d y sit e  h as  a  Cli ni c al  Tri al  A gr e e m e nt i n  pl a c e.  
4.   St u d y sit e  p ers o n n el, i n cl u di n g t h e i n v esti g at or,  h a v e  p arti ci p at e d i n  a st u d y i niti ati o n 
m e eti n g.  
1 4. 3.   
St u d y  D o c u m e nts  
All  d o c u m e nt ati o n  a n d  m at eri al  pr o vi d e d  b y t h e s p o ns or f or t his st u d y  ar e t o  b e r et ai n e d i n  a 
s e c ur e l o c ati o n  a n d tr e at e d  as  c o nfi d e nti al  m at eri al.  
1 4. 3. 1.   
G o o d  Cli ni c al  P r a cti c e  D o c u m e nts  
T h e  G C P  d o c u m e nts  ar e list e d  b el o w. 
•   Si g n e d  ori gi n al  pr ot o c ol (i. e., I n v esti g at or’s  A gr e e m e nt) 
•   C urri c ul a  vit a e  of  all i n v esti g at o rs  a n d s u b-i n v esti g at ors 
•   N a m e  a n d  a d dr ess  of t h e l a b or at ori es  
•   List  of l a b or at or y r ef er e n c e r a n g es,  a n d if  a v ail a bl e,  a  q u alit y  c ertifi c at e  
•   Si g n at ur e  L o g/ D el e g ati o n  of  St u d y- r el at e d  D uti es 
•   F D A  F or m  1 5 7 2 
•   A n y  ot h er r el e v a nt  G C P  d o c u m e nts 
T h e  G C P  d o c u m e nts  m ust  b e r e c ei v e d fr o m t h e i n v esti g at or  a n d r e vi e w e d  a n d  a p pr o v e d  b y t h e 
s p o ns or  or  d esi g n e e  b ef or e t h e st u d y sit e  c a n i niti at e t h e st u d y  a n d  b ef or e t h e s p o ns or  will 
a ut h ori z e s hi p m e nt  of st u d y  dr u g t o t h e st u d y sit e.   C o pi es  of t h e i n v esti g at or’s  G C P  d o c u m e nt s 
m ust  b e r et ai n e d  at t h e st u d y sit e i n  a s e c ur e l o c ati o n.   A d diti o n al  d o c u m e nts, i n cl u di n g  a  c o p y  of 
t h e  pr ot o c ol  a n d  a p pli c a bl e  a m e n d m e nt(s), t h e st u d y  dr u g,  C R F  c o m pl eti o n  g ui d eli n es,  c o pi es  of 
r e g ul at or y r ef er e n c es,  c o pi es  of I R B  c orr es p o n d e n c e,  a n d st u d y  dr u g  a c c o u nt a bilit y r e c or ds 
s h o ul d  als o  b e r et ai n e d  as  p art  of t h e i n v esti g at or’s  G C P  d o c u m e nts.  It is t h e i n v esti g at or’s 
r es p o nsi bilit y t o  e ns ur e t h at  c o pi es  of  all r e q uir e d  G C P  d o c u m e nts  ar e  or g a ni z e d,  c urr e nt,  a n d 
a v ail a bl e f or i ns p e cti o n.  
1 4. 3. 2.   
C as e  R e p o rt  F o r ms  
B y si g ni n g t h e I n v esti g at or’s  A gr e e m e nt, t h e i n v esti g at or  a gr e es t o  m ai nt ai n  a c c ur at e  C R Fs  a n d 
s o ur c e  d o c u m e nt ati o n  as  p art  of t h e  c as e  hist ori es f or  all s u bj e cts  w h o  si g n  a n i nf or m e d  c o ns e nt 
f or m. 
C as e r e p ort f or ms  ar e  c o nsi d er e d  c o nfi d e nti al  d o c u m e nts  a n d s h o ul d  b e  h a n dl e d  a n d st or e d 
a c c or di n gl y.   T h e s p o ns or  or its  d esi g n e e  will  pr o vi d e t h e  n e c ess ar y tr ai ni n g  o n t h e  us e  of t h e 
s p e cifi c  C R F s yst e m  us e d  d uri n g t h e st u d y t o  e ns ur e t h at t h e st u d y i nf or m ati o n is  c a pt ur e d 
a c c ur at el y  a n d  a p pr o pri at el y . 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 3  of  7 4  
T o  e ns ur e  d at a  a c c ur a c y,  C R F  d at a f or i n di vi d u al s u bj e ct  visits s h o ul d  b e  c o m pl et e d  as s o o n  as 
p ossi bl e  aft er t h e  visit.   All r e q u est e d i nf or m ati o n  m ust  b e  e nt er e d i n t h e  C R F  a c c or di n g t o t h e 
c o m pl eti o n  g ui d eli n es  pr o vi d e d  b y t h e s p o ns or  or its  d esi g n e e. 
T h e  C R Fs  m a y  b e si g n e d  b y t h e i n v esti g at or  or  a s u b-i n v esti g at or.   T h es e si g n at ur es s er v e t o 
att est t h at t h e i nf or m ati o n  c o nt ai n e d i n t h e  C R F is  a c c ur at e  a n d tr u e.  
1 4. 3. 3.   
S o u r c e  D o c u m e nts  
All i nf or m ati o n r e c or d e d i n t h e  C R F  m ust  b e s u p p ort e d  b y  c orr es p o n di n g s o ur c e  d o c u m e nt ati o n.  
E x a m pl es  of  a c c e pt a bl e s o ur c e  d o c u m e nt ati o n i n cl u d e,  b ut  ar e  n ot li mit e d t o,  h os pit al r e c or ds, 
cli ni c  a n d  offi c e  c h arts, l a b or at or y  n ot es,  a n d r e c or d e d  d at a fr o m  a ut o m at e d i nstr u m e nts, 
m e m or a n d a,  a n d  p h ar m a c y  dis p e nsi n g  r e c or ds. 
D uri n g t h e st u d y, s el e ct  C R F  d at a  m a y  b e  us e d  as  ori gi n al  d at a  c oll e cti o n t o ols  as l o n g  as  a 
d es cri pti o n  of t his  d o c u m e nt ati o n  pr o c ess is  m ai nt ai n e d i n t h e i n v esti g at or’s st u d y fil es.   B ef or e 
t h e st u d y st arts,  a list i d e ntif yi n g  a n y  d at a t o  b e r e c or d e d  dir e ctl y  o n t h e  C R Fs (i. e.,  n o  pri or 
writt e n  or  el e ctr o ni c r e c or d  of  d at a)  a n d  c o nsi d er e d t o  b e s o ur c e  d at a  will  b e  pr o vi d e d. 
1 4. 4.   
D at a  Q u alit y  C o nt r ol  
T h e s p o ns or  a n d its  d esi g n e es  will  p erf or m  q u alit y  c o ntr ol  c h e c ks  o n t his  cli ni c al st u d y. 
1 4. 4. 1.   
M o nit o ri n g  P r o c e d u r es  
T h e s p o ns or  or  d esi g n e e  will  c o n d u ct sit e  visits t o  m o nit or t h e st u d y  a n d  e ns ur e  c o m pli a n c e  wit h 
t h e  pr ot o c ol,  G C P,  a n d  a p pli c a bl e r e g ul ati o ns  a n d  g ui d eli n es.   T h e  assi g n e d  cli ni c al r es e ar c h 
ass o ci at e ( C R A)  will  visit t h e i n v esti g at or  a n d st u d y sit e  at  p eri o di c i nt er v als  a n d  m ai nt ai n 
p eri o di c  c o m m u ni c ati o n.   T h e i n v esti g at or  a gr e es t o  all o w t h e  C R A  a n d  ot h er  a ut h ori z e d s p o ns or 
p ers o n n el  a c c ess.   T h e  C R A  will  m ai nt ai n  c urr e nt  p ers o n al  k n o wl e d g e  of t h e st u d y t hr o u g h 
o bs er v ati o n, r e vi e w  of st u d y r e c or ds  a n d s o ur c e  d o c u m e nt ati o n,  a n d  dis c ussi o n  of t h e  c o n d u ct  of 
t h e st u d y  wit h t h e i n v esti g at or  a n d st aff.  W hil e  o n sit e, t h e  C R A  will r e vi e w:  
•   R e g ul at or y  d o c u m e nts,  dir e ctl y  c o m p ari n g  e ntri es i n t h e  C R F  wit h t h e s o ur c e  d o c u m e nts 
•   C o ns e nti n g  pr o c e d ur es 
•   A E  pr o c e d ur es  
•   St or a g e  a n d  a c c o u nt a bilit y  of st u d y  dr u g  a n d st u d y  m at eri als 
T h e  C R A  will  as k f or  cl arifi c ati o n  or  c orr e cti o n  of  a n y  n ot e d i n c o nsist e n ci es.   Pr o c e d ur es f or 
c orr e cti n g  C R Fs  ar e  d es cri b e d i n t h e st u d y  m a n u al.   As r e pr es e nt ati v es  of t h e s p o ns or,  C R As  ar e 
r es p o nsi bl e f or  n otif yi n g  pr oj e ct  m a n a g e m e nt  of  a n y  n ot e d  pr ot o c ol  d e vi ati o ns. 
B y si g ni n g t h e I n v esti g at or’s  A gr e e m e nt, t h e i n v esti g at or  a gr e es t o  m e et  wit h t h e  C R A  d uri n g 
st u d y sit e  visits; t o  e ns ur e t h at st u d y st aff is  a v ail a bl e t o t h e  C R A  as  n e e d e d ; t o  pr o vi d e t h e  C R A 
a c c ess t o  all st u d y  d o c u m e nt ati o n, t o t h e  cli ni c al s u p pli es  dis p e nsi n g  a n d st or a g e  ar e a;  a n d t o 
assist t h e  m o nit ors i n t h eir  a cti viti es, if r e q u est e d.   F urt h er, t h e i n v esti g at or  a gr e es t o  all o w t h e 
s p o ns or  or  d esi g n e e  a u dit ors  or i ns p e ct ors fr o m r e g ul at or y  a g e n ci es t o r e vi e w r e c or ds  a n d t o 
assist t h e i ns p e ct ors i n t h eir  d uti es, if r e q u est e d.  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 4  of  7 4  
1 4. 4. 2.   
D at a  M a n a g e m e nt 
T h e s p o ns or  or  d esi g n e e  will  b e r es p o nsi bl e f or  a cti viti es  ass o ci at e d  wit h t h e  d at a  m a n a g e m e nt 
of t his st u d y.   T h e st a n d ar d  pr o c e d ur es f or  h a n dli n g  a n d  pr o c essi n g r e c or ds  will  b e f oll o w e d  p er 
G C P  a n d t h e s p o ns or’s  or  c o ntr a ct r es e ar c h  or g a ni z ati o n’s ( C R O) st a n d ar d  o p er ati n g  pr o c e d ur es.  
A  c o m pr e h e nsi v e  d at a  m a n a g e m e nt  pl a n  will  b e  d e v el o p e d i n cl u di n g  a  d at a  m a n a g e m e nt  pl a n, 
d at a b as e  c o nt e nts,  a n n ot at e d  C R F, s elf- e vi d e nt  c orr e cti o n  c o n v e nti o ns,  q u er y  c o nt a cts,  a n d 
c o nsist e n c y  c h e c ks. 
St u d y sit e  p ers o n n el  will  b e r es p o nsi bl e f or  pr o vi di n g r es ol uti o ns t o  all  d at a  q u eri es.   T h e 
i n v esti g at or  will  b e r e q uir e d t o  d o c u m e nt  d at a r e vi e w t o  e ns ure t h e  a c c ur a c y  of t h e  c orr e ct e d 
a n d/ or  cl arifi e d  d at a.   Pr o c e d ur es f or s oli citi n g  a n d  d o c u m e nti n g r es ol uti o n t o  d at a  q u eri es  ar e 
d es cri b e d i n t h e  D at a  M a n a g e m e nt  Pl a n.  
1 4. 4. 3.   
Q u alit y  Ass u r a n c e/ A u dit  
T his st u d y  m a y  b e s u bj e ct t o  a u dit  b y t h e s p o ns or  or  d esi g n e e.   T h e  a u dits  m a y  b e  u n d ert a k e n t o 
c h e c k  c o m pli a n c e  wit h  G C P  g ui d eli n es  a n d  m a y i n cl u d e: 
•   I n- h o us e st u d y fil e  a u dit 
•   A u dit  of  c o m p ut er  d at a b as e  q u alit y  c o ntr ol 
•   A u dit  of  cli ni c al r e p ort  q u alit y  c o ntr ol 
T h e s p o ns or  or  d esi g n e e  m a y  c o n d u ct  a d diti o n al  a u dits  o n  a s el e cti o n  of st u d y sit es, r e q uiri n g 
a c c ess t o s u bj e ct  n ot es, st u d y  d o c u m e nt ati o n,  a n d f a ciliti es  or l a b or at ori es  us e d f or t h e st u d y. 
T h e st u d y sit e, f a ciliti es,  all  d at a (i n cl u di n g s o ur c e  d at a),  a n d  d o c u m e nt ati o n  will  b e  m a d e 
a v ail a bl e f or  a u dit  b y  q u alit y  ass ur a n c e  a u dit ors  a n d f or I R B  or r e g ul at or y  a ut h oriti es  a c c or di n g 
t o  G C P  g ui d eli n es.   T h e i n v esti g at or  a gr e es t o  c o o p er at e  wit h t h e  a u dit or  d uri n g t h e  visit  a n d  will 
b e  a v ail a bl e t o s u p pl y t h e  a u dit or  wit h  C R Fs  or  ot h er fil es  n e c ess ar y t o  c o n d u ct t h at  a u dit.   A n y 
fi n di n gs  will  b e stri ctl y  c o nfi d e nti al. 
If  a r e g ul at or y  a ut h orit y i nf or ms t h e i n v esti g at or t h at it i nt e n ds t o  c o n d u ct  a n i ns p e cti o n, t h e 
i n v esti g at or s h all  n otif y t h e s p o ns or i m m e di at el y. 
1 4. 5.   
St u d y  T e r mi n ati o n  
T h e st u d y  m a y  b e t er mi n at e d  at t h e  s p o ns or’s  dis cr eti o n  at  a n y ti m e  a n d f or  a n y r e as o n. 
1 4. 5. 1.   
R e g ul a r  St u d y  T e r mi n ati o n  
T h e  e n d  of t his st u d y is  d efi n e d  as t h e  d at e  of t h e l ast  visit  of t h e l ast s u bj e ct (l ast s u bj e ct  o ut  or 
l ast s u bj e ct l ast  visit)  p arti ci p ati n g i n t h e st u d y.   Wit hi n  9 0  d a ys  of t h e  e n d  of t h e  cli ni c al st u d y, 
t h e s p o ns or  or  d esi g n e e  will  n otif y t h e I R B  a n d r e g ul at or y  a ut h oriti es  a b o ut t h e r e g ul ar 
t er mi n ati o n  of t h e st u d y  as r e q uir e d. 
1 4. 5. 2.   
P r e m at u r e  St u d y  T e r mi n ati o n  
T h e st u d y  m a y  b e t er mi n at e d  pr e m at ur el y f or  a n y r e as o n  a n d  at  a n y ti m e  b y t h e s p o ns or, I R B, 
r e g ul at or y  a ut h oriti es,  or t h e  c o or di n ati n g i n v esti g at or.   A  d e cisi o n t o  pr e m at ur el y t er mi n at e t h e 
st u d y is  bi n di n g t o  all i n v esti g at ors  of  all st u d y sit es. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 5  of  7 4  
Wit hi n  1 5  d a ys  of  pr e m at ur e t er mi n ati o n  of  a  cli ni c al st u d y, t h e s p o ns or  or  d e si g n e e  will  n otif y 
t h e I R B  a n d r e g ul at or y  a ut h oriti es  as r e q uir e d.   T h e s p o ns or  or  d esi g n e e  m ust  cl e arl y  e x pl ai n t h e 
r e as o ns f or  pr e m at ur e t er mi n ati o n. 
If t h e st u d y is t er mi n at e d  pr e m at ur el y,  all i n v esti g at ors  m ust i nf or m t h eir s u bj e cts  a n d t a k e  c ar e 
of  a p pr o pri at e f oll o w- u p  a n d f urt h er tr e at m e nt  of s u bj e cts t o  e ns ur e  pr ot e cti o n  of t h e s u bj e cts’ 
i nt er ests.   St u d y sit es  m a y  b e  as k e d t o  h a v e  all s u bj e cts  c urr e ntl y  p arti ci p ati n g i n t h e st u d y 
c o m pl et e  all  of t h e  ass ess m e nts f or t h e  E arl y  T er mi n ati o n  visit.  
1 4. 6.   
St u d y  Sit e  Cl os u r e  
At t h e  e n d  of t h e st u d y,  all st u d y sit es  will  b e  cl os e d.  T h e s p o ns or  m a y t er mi n at e  p arti ci p ati o n  of 
a st u d y sit e  at  a n y ti m e.   E x a m pl es  of  c o n diti o ns t h at  m a y r e q uir e  pr e m at ur e t er mi n ati o n  of  a 
st u d y sit e i n cl u d e,  b ut  ar e  n ot li mit e d t o, t h e f oll o wi n g: 
•   N o n c o m pli a n c e  wit h t h e  pr ot o c ol,  wit h  a p pli c a bl e r e g ul ati o ns  a n d  g ui d eli n es,  or  b ot h. 
•   I n a d e q u at e s u bj e ct  e nr oll m e nt. 
1 4. 6. 1.   
R e c o r d  R et e nti o n  
T h e i n v esti g at or s h all r et ai n  a n d  pr es er v e  o n e  c o p y  of  all  d at a  g e n er at e d i n t h e  c o urs e  of t h e 
st u d y, s p e cifi c all y i n cl u di n g,  b ut  n ot li mit e d t o, t h os e  d efi n e d  b y  G C P  as  ess e nti al  u ntil  at l e ast 
2  y e ars  aft er t h e  n otifi c ati o n  of s u b missi o n  of t h e fi n al  C S R  t o r e g ul at or y  a ut h oriti es  b y t h e 
s p o ns or. 
T h es e  d o c u m e nts s h o ul d  b e r et ai n e d f or  a l o n g er  p eri o d,  h o w e v er, if r e q uir e d  b y t h e  a p pli c a bl e 
r e g ul at or y r e q uir e m e nt(s)  or if  n e e d e d  b y t h e s p o ns or. 
At t h e  e n d  of s u c h  p eri o d, t h e i n v esti g at or s h all  n otif y t h e s p o ns or i n  writi n g  of  his  or  h er i nt e nt 
t o  d estr o y  all s u c h  m at eri al.  T h e s p o ns or s h all  h a v e  3 0  d a ys t o r es p o n d t o t h e i n v esti g at or’s 
n oti c e,  a n d t h e s p o ns or s h all  h a v e  a f urt h er  o p p ort u nit y t o r et ai n s u c h  m at eri als  at t h e s p o ns or’s 
e x p e ns e.  
Aft er  c o m pl eti n g  t h e st u d y, t h e s p o ns or  will  b e  pr o vi d e d  wit h t h e  ori gi n al  C R Fs  or  at l e ast  a 
l e gi bl e  c o p y  a n d r et ai n t h e  d o c u m e nts  at l e ast  5  y e ars  aft er t h e  c o m pl eti o n  of t h e st u d y. 
O n e   c o p y  will r e m ai n  wit h t h e i n v esti g at or.   T h e i n v esti g at or s h all  arr a n g e f or t h e r et e nti o n  of 
t h e s u bj e ct i d e ntifi c ati o n  c o d es, s u bj e ct fil es,  a n d  ot h er s o ur c e  d at a  u ntil  at l e ast  5  y e ars  aft er 
n otifi c ati o n  of s u b missi o n  of t h e fi n al  C S R  t o t h e r e g ul at or y  a ut h oriti es  b y t h e s p o ns or.   T h es e 
d o c u m e nts  n e e d t o  b e r et ai n e d f or  a l o n g er  p eri o d if r e q uir e d  b y  a p pli c a bl e r e g ul at or y  a ut h oriti es 
or  b y  a gr e e m e nt  wit h t h e s p o ns or. 
At t h e  e n d  of s u c h  p eri o d, t h e i n v esti g at or s h all  n otif y t h e s p o ns or i n  writi n g  of  his  or  h er i nt e nt 
t o  d estr o y  all s u c h  m at eri al.  T h e s p o ns or s h all  h a v e  3 0  d a ys t o r es p o n d t o t h e i n v esti g at or’s 
n oti c e,  a n d t h e s p o ns or s h all  h a v e  a f urt h er  o p p ort u nit y t o r et ai n s u c h  m at eri als  at t h e s p o ns or’s 
e x p e ns e.  
C o pi es  of t h es e st u d y r e c or ds ( a n d  all st u d y-r el at e d  d o c u m e nts, i n cl u di n g s o ur c e  d at a) s h all  b e 
k e pt  b y t h e i n v esti g at or f or t h e  m a xi m u m  p eri o d  p er mitt e d  b y t h e  h os pit al, i nstit uti o n,  or  pri v at e 
pr a cti c e.  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 6  of  7 4  
1 4. 6. 2.   
S a m pl e  R et e nti o n  
S a m pl es  m a y  b e  us e d f or  p ur p os es r el at e d t o t his r es e ar c h.   T h e s a m pl es  will  b e st or e d  u ntil t h e 
s p o ns or  h as  d et er mi n e d t h at s p e ci m e ns  ar e  n o l o n g er  n e e d e d,  a n d  t h e  d e cisi o n  h as  b e e n  m a d e 
t h at  n o n e  of t h e s a m pl es  n e e ds t o  b e r e a n al y z e d  or  at t h e  c o m pl eti o n  of t h e  C S R.  I n  a d diti o n, 
i d e ntifi a bl e s a m pl es  c a n  b e  d estr o y e d  at  a n y ti m e  at t h e r e q u est  of t h e s u bj e ct. 
1 4. 7.   
C h a n g es t o t h e  P r ot o c ol  
T his  pr ot o c ol  c a n n ot  b e  alt er e d  or  c h a n g e d  e x c e pt t hr o u g h  a f or m al  pr ot o c ol  a m e n d m e nt,  w hi c h 
r e q uir es t h e  writt e n  a p pr o v al  b y t h e s p o ns or.   T h e  pr ot o c ol  a m e n d m e nt  m ust  b e si g n e d  b y t h e 
i n v esti g at or  a n d  a p pr o v e d  b y t h e I R B  b ef or e it  m a y  b e i m pl e m e nt e d.   Pr ot o c ol  a m e n d m e nts  will 
b e fil e d  wit h t h e  a p pr o pri at e r e g ul at or y  a g e n c y. 
1 4. 8.   
Us e  of I nf o r m ati o n  
All i nf or m ati o n  a b o ut t h e st u d y  dr u g, t h e s p o ns or’s  o p er ati o ns,  p at e nt  a p pli c ati o ns, f or m ul as, 
m a n uf a ct uri n g  pr o c ess es,  b asi c s ci e ntifi c  d at a,  a n d f or m ul ati o n i nf or m ati o n s u p pli e d  b y t h e 
s p o ns or  or  d esi g n e e t o t h e i n v esti g at or  a n d  n ot  pr e vi o usl y  p u blis h e d, is  c o nsi d er e d  c o nfi d e nti al 
a n d r e m ai ns t h e s ol e  pr o p ert y  of t h e s p o ns or.   C as e r e p ort f or ms  als o r e m ai n t h e  pr o p ert y  of t h e 
s p o ns or.   T h e i n v esti g at or  a gr e es t o  us e t his i nf or m ati o n f or  p ur p os es  of st u d y  e x e c uti o n t hr o u g h 
fi n ali z ati o n  a n d  will  n ot  us e it f or  ot h er  p ur p os es  wit h o ut t h e  writt e n  c o ns e nt  of t h e s p o ns or. 
T h e i nf or m ati o n  d e v el o p e d i n t his st u d y  will  b e  us e d  b y t h e s p o ns or i n  c o n n e cti o n  wit h t h e 
c o nti n u e d  d e v el o p m e nt  of t h e st u d y  dr u g  a n d t h us  m a y  b e  dis cl os e d  as r e q uir e d t o  ot h er  cli ni c al 
i n v esti g at ors  or  g o v er n m e nt r e g ul at or y  a g e n ci es. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 7  of  7 4  
1 5.   
FI N A L  C LI NI C A L  S T U D Y  R E P O R T  
T h e fi n al  C S R   will  b e  writt e n  a c c or di n g t o t h e  “ G ui d eli n e f or I n d ustr y ( Str u ct ur e  a n d  C o nt e nt  of 
Cli ni c al  St u d y  R e p orts) ” fr o m t h e I C H  E 3.   T h e fi n al  C S R   will  pr es e nt  a  n arr ati v e  d es cri pti o n  of 
t h e  cli ni c al,  a n al yti c al, P K ,  a n d st atisti c al r es ults.   T a bl es  a n d fi g ur es will  b e  “i nt e gr at e d ” i nt o t h e 
m ai n t e xt,  wit h  a p p e n di c es  at t h e  e n d  of t h e r e p ort ( e. g., t h e  pr ot o c ol, s a m pl e  C R Fs, i n v esti g at or-
r el at e d i nf or m ati o n, t est/r ef er e n c e  pr o d u ct i nf or m ati o n, s u bj e ct  d at a listi n gs). 
T h e fi n al  C S R  will  b e s u b mitt e d t o t h e  a p pr o pr i at e r e g ul at or y  a ut h oriti es. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 8  of  7 4  
1 6.   
E T HI C A L  A N D  L E G A L  C O N SI D E R A TI O N S  
1 6. 1.   
D e cl a r ati o n  of  H elsi n ki  a n d  G o o d  Cli ni c al  P r a cti c e  
T his st u d y  will  b e  c o n d u ct e d i n  c o m pli a n c e  wit h t h e  N o v e m b er  2 0 1 6 I C H  G ui d a n c e f or I n d ustr y 
E 6( R 2)  G C P  a n d t h e  1 9 9 6  V ersi o n  of t h e  D e cl ar ati o n  of  H elsi n ki. 
1 6. 2.   
S u bj e ct I nf o r m ati o n  a n d I nf o r m e d  C o ns e nt  
A  pr o p erl y  c o nstit ut e d,  v ali d I R B  m ust r e vi e w  a n d  a p pr o v e t h e  pr ot o c ol, t h e i n v esti g at or’s 
i nf or m e d  c o ns e nt  d o c u m e nt,  a n d r el at e d s u bj e ct i nf or m ati o n  a n d r e cr uit m e nt  m at eri als  b ef or e t h e 
st art  of t h e stu d y. 
It is t h e r es p o nsi bilit y  of t h e i n v esti g at or t o  e ns ur e t h at i nf or m e d  c o ns e nt  h as  b e e n  o bt ai n e d fr o m 
t h e s u bj e ct  or  L A R  b ef or e  a n y  a cti vit y  or  pr o c e d ur e is  u n d ert a k e n t h at is  n ot  p art  of r o uti n e  c ar e. 
1 6. 3.   
A p p r o v al  b y I nstit uti o n al  R e vi e w  B o a r d  
A  v ali d I R B  m ust r e vi e w  a n d  a p pr o v e t his  pr ot o c ol  b ef or e st u d y i niti ati o n.   Writt e n  n otifi c ati o n 
of  a p pr o v al is t o  b e s u b mitt e d  b y t h e i n v esti g at or t o t h e s p o ns or  m o nit or  b ef or e s hi p m e nt  of 
i n v esti g ati o n al  dr u g s u p pli es a n d  will i n cl u d e t h e  d at e  of t h e  c o m mitt e e’s  a p p r o v al  a n d t h e 
c h air p ers o n’s si g n at ur e.   T his  writt e n  a p pr o v al  m ust  c o nsist  of  a  c o m pl et e d s p o ns or I R B 
A p pr o v al  F or m  or  writt e n  d o c u m e nt ati o n fr o m t h e I R B  c o nt ai ni n g t h e s a m e i nf or m ati o n. 
U ntil  writt e n  a p pr o v al  b y t h e I R B  h as  b e e n r e c ei v e d  b y t h e i n v esti g at or,  n o s u bj e ct  m a y  u n d er g o 
a n y  pr o c e d ur e s ol el y f or  d et er mi ni n g  eli gi bilit y f or t his st u d y. 
Pr ot o c ol  a m e n d m e nts  m ust  als o  b e r e vi e w e d  a n d  a p pr o v e d  b y t h e I R B.   Writt e n  a p pr o v al fr o m 
t h e I R B,  or  a  d esi g n e e,  m ust  b e r e c ei v e d  b y t h e s p o ns or  b ef or e i m pl e m e nt ati o n.   T his  writt e n 
a p pr o v al  will  c o nsist  of  a  c o m pl et e d I R B  A p pr o v al f or m  or  writt e n  d o c u m e nt ati o n fr o m t h e I R B 
c o nt ai ni n g t h e s a m e i nf or m ati o n. 


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  6 9  of  7 4  
1 7.   
R E F E R E N C E S  
Al d erf er  B S,  All e n  M H.  Tr e at m e nt  of  A git ati o n i n  Bi p ol ar  Dis or d er  A cr oss t h e  Lif e  C y cl e. J 
Cli n  Ps y c hi atr y.  2 0 0 3;  6 4 ( S u p pl  4):  3- 9. 
All e n,  M  H,  C urri er,  G  W,  H u g h es,  D  H,  R e y es- H ar d e,  M,  D o c h ert y, J  P.  T h e  E x p ert  C o ns e ns us 
G ui d eli n e  S eri es.  Tr e at m e nt  of  b e h a vi or al  e m er g e n ci es.  P ost gr a d u at e  m e di ci n e.  2 0 0 1;( S p e c 
N o): 1 - 8 8. 
All e n  M H,  C urri er  G W,  H u g h es  D H,  D o c h ert y J P,  C ar p e nt er  D,  R oss  R.  Tr e at m e nt  of 
B e h a vi or al  E m er g e n ci es:  A  S u m m ar y  of t h e  E x p ert  C o ns e ns us  G ui d eli n es. J o ur n al  of  Ps y c hi atri c 
Pr a cti c e.  2 0 0 3;  9:  1 6 – 3 8. 
All e n  M H,  F eif el  D,  L es e m  M D,  Zi m br off  D L,  R oss  R,  M u n z ar  P,  S p y k er  D A,  C ass ell a J V. 
Effi c a c y  a n d  S af et y  of  L o x a pi n e f or I n h al ati o n i n t h e  Tr e at m e nt  of  A git ati o n i n  P ati e nts  wit h 
S c hi z o p hr e ni a:  A  R a n d o mi z e d,  D o u bl e- Bli n d,  Pl a c e b o- C o ntr oll e d  Tri al. J  Cli n  Ps y c hi atr y.  2 0 1 1: 
7 2;  1 0:  1 3 1 3- 1 3 2 1. 
B att a gli a J.  P h ar m a c ol o gi c al  M a n a g e m e nt  of  A c ut e  A git a ti o n.  Dr u gs.  2 0 0 5;  6 5 ( 9):  1 2 0 7- 1 2 2 2. 
C o n n  D K,  Li eff  S.  Di a g n osi n g  a n d  M a n a gi n g  D eliri u m i n t h e  El d erl y.  C a n  F a m  P h ysi ci a n.  2 0 0 1; 
4 7:  1 0 1- 1 0 8. 
C urri er  G W,  Tr e nt o n  A.  P h ar m a c ol o gi c al  Tr e at m e nt  of  Ps y c h oti c  A git ati o n.  C N S  Dr u gs.  2 0 0 2; 
1 6 ( 4):  2 1 9- 2 2 8. 
C urri e r  G W,  All e n  M H,  B u n n e y  E B,  D a ni el  D G,  Fr a n cis  A, J a g o d a  A,  Zi m br off  D.  St a n d ar d 
T h er a pi es f or  A c ut e  A git ati o n. J o ur n al  of  E m er g e n c y  M e di ci n e.  2 0 0 4;  V ol.  2 7:  S 9 – S 1 2. 
M H R A.  C L H  R e p ort:  Pr o p os al f or  H ar m o nis e d  Cl assifi c ati o n  a n d  L a b elli n g,  S u bst a n c e  N a m e: 
M e d et o mi di n e.  O ct o b er  2 0 1 4.  V ersi o n  1. 
O q u e n d o  M A,  H al b erst a m  B,  M a n n JJ.  C ol o m bi a  S ui ci d e  S e v erit y  R ati n g  S c al e ( C- S S R S)  – 
Ris k  F a ct ors f or  S ui ci d al  B e h a vi or:  T h e  Utilit y  a n d  Li mit ati o ns  of  R es e ar c h I nstr u m e nts, i n 
St a n d ar di z e d  E v al u ati o n i n  Cli ni c al  Pr a cti c e.  First  M B,  e dit or.  A m eri c a n  P s y c hi atri c  P u blis hi n g; 
W as hi n gt o n,  D C:  2 0 0 3:  1 0 3- 1 3 1. 
Oss er  D N,  Si g a d el  R,  S h ort- T er m I n p ati e nt  P h ar m a c ot h er a p y  of  S c hi z o p hr e ni a.  H ar v ar d  R e vi e w 
of  Ps y c hi atr y.  M a y-J u n e  2 0 0 1;  V ol u m e  9 (Iss u e  3):  8 9- 1 0 4. 
S al z m a n  C, J est e  D V,  M e y er  R E,  C o h e n- M a nsfi el d J,  C u m mi n gs J,  Gr oss b er g  G T,  et  al.  El d erl y 
p ati e nts  wit h  d e m e nti a -r el at e d s y m pt o ms  of s e v er e  a git ati o n  a n d  a g gr essi o n:  C o ns e ns us 
st at e m e nt  o n tr e at m e nt  o pti o ns,  cli ni c al tri als  m et h o d ol o g y,  a n d  p oli c y.  J o ur n al  of  Cli ni c al 
Ps y c hi atr y.  2 0 0 8,  M a y  1 3;  6 9:  8 8 9- 8 9 8. 
Pr e c e d e x.  U S  P a c k a g e I ns ert.  2 0 1 6  M a y.  


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  7 0  of  7 4  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  7 1  of  7 4  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V er si o n 7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  7 2  of  7 4  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  7 3  of  7 4  
C CI


Bi o X c el  T h er a p e uti cs, I n c.    
   
  
C o nfi d e nti al    
   
   
  
B X C L 5 0 1 -1 0 3  
 
Pr ot o c ol  B X C L 5 0 1 -1 0 3  –  V ersi o n  7 , 0 4  F e b  2 0 2 1       
   
   
   
  
P a g e  7 4  of  7 4  
C CI

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
A PHASE Ib/II, MULTICENTER, RANDOMIZED, 
DOUBLE BLIND, PLACEBO CONTROLLED, 
ASCENDING DOSE FINDING, EFFICACY, 
PHARMACOKINETIC AND SAFETY STUDY OF 
BXCL501 IN AGITATION ASSOCIATED WITH 
DEMENTIA 
 
NCT04251910 
04/28/2020 


BioXcel Therapeutics, Inc. 
Protocol BXCL501-103 
Statistical Analysis Plan: Final Version 1.0 April 28, 2020 
Page | 1 
STATISTICAL ANALYSIS PLAN 
PROTOCOL: BXCL501-103 
A Phase Ib/II, Multicenter, Randomized, Double Blind, 
Placebo Controlled, Ascending Dose Finding, Efficacy, 
Pharmacokinetic and Safety Study of BXCL501 in 
Agitation Associated with Dementia
SPONSOR: 
BioXcel Therapeutics, Inc. 
555 Long Wharf Drive 
12th Floor 
New Haven, CT 06511 
PRODUCT: 
BXCL501 
AUTHOR: 
, 
 
Lead Statistician 
Cognitive Research Corporation 
200 Central Ave. Suite 1230 
Saint Petersburg, Florida 33701 
DATE: 
28 April 2020 
STATUS: 
Final Version 1.0 
PPD
PPD




 
 
BioXcel Therapeutics, Inc. 
 
 
Protocol BXCL501-103 
 
 
Statistical Analysis Plan: Final Version 1.0 April 28, 2020 
Page | 3 
TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................... 3 
AMENDMENT HISTORY ...................................................................................... 5 
1 LIST OF ABBREVIATIONS ............................................................................ 5 
2 INTRODUCTION ............................................................................................. 7 
3 STUDY OBJECTIVES ..................................................................................... 7 
3.1 PRIMARY OBJECTIVE ............................................................................................ 7 
3.2 SECONDARY OBJECTIVES ................................................................................... 7 
4 STUDY DESIGN .............................................................................................. 8 
4.1 DURATION OF STUDY ............................................................................................ 8 
4.2 NUMBER OF PARTICIPANTS (STUDY POPULATION) ......................................... 8 
4.3 DESIGN .................................................................................................................... 8 
4.3.1 
SCHEDULE OF EVENTS AND ASSESSMENTS ............................................................. 10 
4.4 TREATMENT .......................................................................................................... 13 
4.5 RANDOMIZATION ................................................................................................. 13 
5 OUTCOME VARIABLE DEFINITIONS ......................................................... 13 
5.1 PRE-SCREENING, SCREENING, AND BASELINE CHARACTERISTICS ........... 13 
5.2 EFFICACY ASSESSMENTS .................................................................................. 14 
5.2.1 
PANSS-EXCITED COMPONENT (PEC) .......................................................................... 14 
5.2.2 
COHEN MANSFIELD AGITATION INVENTORY (CMAI) ................................................. 14 
5.2.3 
AGITATION-CALMNESS EVALUATION SCALE (ACES) ................................................ 14 
5.2.4 
PITTSBURG AGITATION SCALE (PAS) .......................................................................... 14 
5.2.5 
CGI-S AND CGI-I FOR AGITATION ................................................................................. 14 
5.3 SAFETY AND TOLERABILITY ASSESSMENTS ................................................... 15 
5.3.1 
ADVERSE EVENTS .......................................................................................................... 16 
5.3.2 
COLUMBIA SUICIDE SEVERITY RATING SCALE .......................................................... 16 
5.3.3 
LABORATORY SAFETY ASSESSMENTS ....................................................................... 16 
5.3.4 
VITAL SIGNS..................................................................................................................... 16 
5.3.5 
ELECTROCARDIOGRAM ................................................................................................. 17 
5.3.6 
PHYSICAL EXAMINATION ............................................................................................... 17 
5.3.7 
BUCCAL ASSESSMENTS ................................................................................................ 17 
5.4 CLINICAL DIAGNOSIS AND DESCRIPTION OF DEMENTIA ............................... 17 
5.4.1 
MMSE ................................................................................................................................ 18 
5.4.2 
CDR ................................................................................................................................... 18 
5.5 PHARMACOKINETICS .......................................................................................... 18 
5.6 CONCOMITANT MEDICATIONS ........................................................................... 18 
6 STUDY ENDPOINTS ..................................................................................... 19 
6.1 PRIMARY ENDPOINTS ......................................................................................... 19 
6.1.1 
PRIMARY EFFICACY ENDPOINT .................................................................................... 19 
6.1.2 
PRIMARY EFFICACY TIME POINT .................................................................................. 19 
6.1.3 
PRIMARY SAFETY AND TOLERABILITY ENDPOINTS .................................................. 19 
6.2 SECONDARY ENDPOINTS ................................................................................... 19 
6.2.1 
SECONDARY EFFICACY ENDPOINTS ........................................................................... 19 
6.2.2 
SECONDARY SAFETY AND TOLERABILITY ENDPOINTS ........................................... 19 
6.2.3 
SECONDARY PHARMACOKINETIC ENDPOINTS.......................................................... 19 
6.3 EXPLORATORY ENDPOINTS ............................................................................... 19 


 
 
BioXcel Therapeutics, Inc. 
 
 
Protocol BXCL501-103 
 
 
Statistical Analysis Plan: Final Version 1.0 April 28, 2020 
Page | 4 
7 STATISTICAL ANALYSES ........................................................................... 20 
7.1 STATISTICAL METHODOLOGY ........................................................................... 20 
7.1.1 
SAMPLE SIZE DETERMINATION .................................................................................... 20 
7.1.2 
POPULATIONS FOR STATISTICAL ANALYSIS .............................................................. 20 
7.1.3 
STATISTICAL ANALYSES – GENERAL CONSIDERATIONS ......................................... 20 
7.1.4 
PROCEDURES FOR HANDLING MISSING DATA .......................................................... 20 
7.1.5 
INTERIM ANALYSES ........................................................................................................ 21 
7.2 SCREENING AND BASELINE CHARACTERISTICS ............................................ 21 
7.3 SUBJECT DISPOSITION ....................................................................................... 22 
7.4 STUDY TREATMENT ADMINISTRATION ............................................................. 22 
7.5 EFFICACY ANALYSES .......................................................................................... 22 
7.5.1 
PRIMARY EFFICACY ANALYSIS ..................................................................................... 22 
7.5.2 
SECONDARY EFFICACY ANALYSES ............................................................................. 23 
7.6 SAFETY ANALYSES .............................................................................................. 23 
7.6.1 
PRIMARY SAFETY ANALYSES ....................................................................................... 24 
7.6.2 
SECONDARY SAFETY ANALYSES ................................................................................. 24 
7.6.3 
ADVERSE EVENTS .......................................................................................................... 24 
7.6.4 
COLUMBIA SUICIDE SEVERITY RATING SCALE .......................................................... 25 
7.6.5 
CLINICAL LABORATORY EVALUATIONS ...................................................................... 26 
7.6.6 
PULSE OXIMETRY ........................................................................................................... 26 
7.6.7 
PHYSICAL EXAMINATION ............................................................................................... 26 
7.6.8 
CLINICAL DIAGNOSIS AND DESCRIPTION OF DEMENTIA ......................................... 26 
7.6.9 
VITAL SIGNS..................................................................................................................... 26 
7.6.10 
12-LEAD ELECTROCARDIOGRAM ............................................................................... 26 
7.6.11 
CONCOMITANT MEDICATIONS .................................................................................... 27 
7.6.12 
STUDY MEDICATION COMPLIANCE ............................................................................ 27 
7.7 PHARMACOKINETIC and PHARMACODYNAMIC ANALYSIS ............................. 27 
8 REFERENCES .............................................................................................. 28 
9 TABLES, LISTINGS AND FIGURES ............................................................ 29 
9.1 TABLES .................................................................................................................. 29 
9.2 LISTINGS ............................................................................................................... 30 
9.3 FIGURES ................................................................................................................ 30 
 


 
 
BioXcel Therapeutics, Inc. 
 
 
Protocol BXCL501-103 
 
 
Statistical Analysis Plan: Final Version 1.0 April 28, 2020 
Page | 5 
AMENDMENT HISTORY 
Not applicable 
1 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACES 
Agitation-Calmness Evaluation Scale 
AE 
Adverse Event 
BMI 
Body Mass Index 
BP 
Blood pressure 
CDR 
Clinical Dementia Rating Scale 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression-Severity 
CMAI 
Cohen Mansfield Agitation Inventory 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
Diastolic blood pressure 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
HR 
Heart rate 
hr 
hour 
ITT 
Intent to Treat 
kg 
kilogram 
µg/µcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
Min 
Minutes 
mL 
milliliter 
mm 
millimeters 
mmHG 
millimeters of mercury 
MMRM 
Mixed model repeated measures 


 
 
BioXcel Therapeutics, Inc. 
 
 
Protocol BXCL501-103 
 
 
Statistical Analysis Plan: Final Version 1.0 April 28, 2020 
Page | 6 
Abbreviation 
Definition 
MMSE 
Mini Mental Status Exam 
PANSS/PANSS-
EC 
Positive and Negative Syndrome Scale/ Positive and Negative 
Syndrome Scale – Excited Component 
PAS 
Pittsburgh Agitation Scale 
PEC 
Positive and Negative Syndrome Scale – Excited Component 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SL 
Sublingual  
SP 
Safety Population  
TFLs 
Tables, Figures, and Listings 
WHO 
World Health Organization 
 
 


 
 
BioXcel Therapeutics, Inc. 
 
 
Protocol BXCL501-103 
 
 
Statistical Analysis Plan: Final Version 1.0 April 28, 2020 
Page | 7 
2 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses for 
the study entitled “A Phase Ib/II, Multicenter, Randomized, Double Blind, Placebo 
Controlled, Ascending Dose Finding, Efficacy, Pharmacokinetic and Safety Study 
of BXCL501 in Agitation Associated with Dementia” (V3 07 December 2019; 
Administrative Letter #1, 14 January 2020; Protocol Clarification Letter #1, 14 
January 2020). All planned pharmacokinetic (PK) analyses will be described in a 
separate PK and PK/PD analysis plan. Mock shells for Appendix 14 of the 
Clinical Study Report (CSR) will also be produced as a separate working 
document to facilitate programming of Tables, Figures, and Listings (TFLs) 
according to the finalized SAP. The SAP is to be interpreted in conjunction with 
the protocol, and supersedes the statistical considerations identified in the 
protocol. If the final clinical study report contains changes to any planned 
statistical analyses, the justification for any such differences will be fully 
documented in the clinical study report (CSR). 
3 
STUDY OBJECTIVES 
3.1 PRIMARY OBJECTIVE 
The primary objective is to describe the safety and tolerability of single doses of 
BXCL501 that may be efficacious in treatment of acute agitation associated with 
dementia.   
3.2 SECONDARY OBJECTIVES 
Secondary objectives are as follows: 
 
• Describe the onset and magnitude of calming effects of different doses of 
BXCL501 on symptoms of acute agitation associated with dementia as 
measured by the Pittsburgh Agitation Scale (PAS) and PANSS-EC (PEC) 
as compared to placebo.  
• Describe the duration of calming as measured by PEC and ACES. 
• Describe the tolerability and safety profile of BXCL501, as determined by 
adverse events and vital signs versus placebo.   
• Describe clinical effects as measured by Clinician Global Impression of 
Severity of agitation scale (CGI-S) and then improvement (CGI-I) after 
drug administration. 
• Describe the frequency of agitated behaviors using the Cohen Mansfield 
Agitation Inventory (CMAI).  
• Determine the approximate time to disappearance of BXCL501 films in the 
sublingual space.  
• Assess the local tolerability via buccal examination after dosing BXCL501 
film. 


 
 
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• Describe the pharmacokinetics and exposure and the potential 
relationship between PK and PD (measures of safety or efficacy) of 
dexmedetomidine as delivered by sublingual BXCL501 dosing. 
4 
STUDY DESIGN 
4.1 DURATION OF STUDY 
The total duration of the study, excluding Screening, will be approximately seven 
days (Day 1 through follow-up). The duration of study treatment 
(BXCL501/placebo) is one day. 
4.2 NUMBER OF PARTICIPANTS (STUDY POPULATION) 
Each cohort will include 10 subjects (8 BXCL501, 2 placebo) enrolled at up to 3 
study sites in the United States. Three cohorts are planned, for a total of 30 
subjects (24 BXCL501, 6 placebo). 
4.3 DESIGN 
This is an adaptive Phase Ib/II trial design. It is a randomized, double-blind, 
placebo-controlled, multiple ascending dose study assessing efficacy, 
pharmacokinetics, safety and tolerability of BXCL501 dosing in adult (65 years 
and older) males and females with acute agitation associated with dementia.  
The study will attempt to characterize a safe and tolerable dose range in at least 
30 subjects, (4:1 randomization to active: placebo) per dose level, at each of the 
three dose levels, that results in a calming effect as measured using the 
Pittsburgh Agitation Scale (PAS). It is possible that the sponsor will opt to expand 
the number of sites and subjects per dose arm as the study progresses.  This 
adaptive design is beneficial as it yields more extensive safety and tolerability 
data, increases confidence in efficacy by capturing variability in response and 
exposure, while providing data that is more generalizable for later phase trials.  
Evaluation of three (3) doses of 30 µg, 60 µg and 90 µg are planned, with an 
option to test different doses based on tolerability and safety. This is an adaptive 
design as doses selected for testing may be different from these, based upon 
safety reviews.  Doses lower or higher may be chosen to test, and repeated, up 
to 180µg within each cohort. BXCL501 films may be divided in half if needed to 
deliver half-dose strengths.  Except for the first dose cohort (30µg), each 
subsequent dose level will be authorized after a safety review of the previous 
dosing cohort.  Dosing may be repeated in the case of persistent or recurrent 
agitation, if there is no significant improvement (CGI-I of 1 or 2 as ‘very much’ or 
‘much improved’) and no safety events evident. Dosing may be repeated up to a 
total of two repeat doses (at the same randomization group Active:Placebo) for 
all cohorts except for 90 µg dose which can only be repeated once (total 180 µg) 
if necessary, at 2 hours post first dose but only after the 2-hour assessments are 
conducted and only within 12 hours post first dose.  Patients can only be re-
dosed if they are hemodynamically stable, not hypotensive (must be greater than 


 
 
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90/60 diastolic/systolic) and not bradycardic (must be greater than 60 bpm). 
Patients also cannot be re-dosed if they are orthostatic (a drop of 20 points in 
either SBP or DBP) or if they are experiencing an AE. Not only does this 
determine individual response to a single dose but determines if a given subject 
is responsive to a second dose, and may respond to a greater dose, or could be 
categorized as a non-responder to BXCL501 despite being exposed to a greater 
total dose.  
Periodic safety data reviews will be undertaken on an ongoing basis to review all 
subjects assigned and dosed, as data and analyses become available. Dose 
escalation will be allowed unless a safety or tolerability issue becomes evident 
upon periodic regular safety review.  
Patients enrolling at a site are sequentially assigned to the lowest dose cohort 
(including placebo) followed by enrollment assignment to increasing dose 
cohorts. This sequential escalating adaptive enrollment ensures subject safety; 
the lowest dose cohort completes accrual first, higher dose cohorts complete 
last. In addition, those subjects assessed as requiring a second dose for efficacy 
provide early evidence of safety/tolerability of higher doses as they are effectively 
exposed to doses that approximate the next dose cohort. The majority of patients 
will be enrolled and evaluated in lower dose cohorts before a higher dose cohort 
is initiated. Further, if evidence of intolerability arises from analyses integrating 
PK, exposure and safety/tolerability of all subjects and doses, the dose regimen 
may be altered, or a different dose may be selected to test the hypothesis that a 
(typically lower) dose regimen is better tolerated. 
In addition to periodic ongoing safety reviews, after accruing each dose cohort a 
safety and tolerability review will be done by the BioXcel Therapeutics, Inc. 
medical monitor, clinical pharmacologist, and the PIs (blinded), who will decide to 
continue or may stop the study. If dose-limiting safety or intolerability is 
determined, further dosing of a cohort may be stopped, and escalation 
discontinued. Further assignment to the same dose will be halted, and escalation 
will be discontinued for the drug-related adverse events specified in the protocol.  
Dose selection criteria are dependent upon the emergent safety and tolerability 
as well as clinical effectiveness. Because these each remain to be tested, 
criterion for dose selection may be adapted as data are acquired (eg, evidence of 
robust efficacy at the lowest tested dose could shift low dose criterion to a higher 
proportion for efficacy).  
Eligible patients (those with any type of dementia) may be identified in SNIFFs, 
mental health, psychiatric or medical emergency services including 
medical/psychiatric observation units, or as newly admitted to a hospital setting 
for acute agitation or already in hospital for chronic underlying conditions. 
Subjects will likely remain in their facility while undergoing screening procedures 
to assess eligibility. Upon confirmation of eligibility, subjects will be randomized 


 
 
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to BXCL501 or placebo film.  At the beginning of each study session, a single 
dose of BXCL501 film will be administered sublingually by the patient if able with 
instructions from an unblinded staff member who will not participate in evaluation 
of safety or efficacy. The drug film will be retained in the sublingual cavity until 
dissolved.  Participants will also be evaluated for local irritation around the area 
where the film is placed.  Efficacy and safety assessments will be conducted 
periodically before and after dosing. The next cohort will be dosed after 
completing accrual of most prior panels, in accord with regular ongoing periodic 
safety and PK review as eligible subjects are assigned, dosed, and data 
becomes available. 
Vital signs and ECGs will be conducted at the time points indicated in the 
schedule of events. Participants will be allowed water as desired 15 minutes after 
completion of dosing.  Safety and tolerability assessments will be continued until 
the morning of Day 3 (day of discharge) and will be repeated on Day 7+2. 
Smoking will be permitted according to the site’s policies. After the 4 hr 
assessments are completed, at the discretion of the PI, rescue therapy may be 
initiated using standard of care treatment which may include lorazepam 0.5-5 mg 
po/IM or an antipsychotic medication po/IM.   
Any abnormal vital sign measurement, clinical laboratory test, physical 
examination finding, or ECG parameter deemed clinically significant by the 
investigator will be repeated, including test results obtained on the final study day 
or upon early termination. For any test abnormality deemed clinically significant, 
repeat analysis will be performed during the follow-up period and until the value 
returns to baseline (or within normal limits) or the investigator deems the 
abnormality to be of no clinical significance. Subjects presenting with a clinically 
significant Urinary Tract Infection (UTI) as determined by clinical laboratory tests 
will be excluded from the study. 
A nurse will be present prior to dosing and remain present for at least 6 hours 
after dosing or longer if needed, until any safety concerns, intolerability or 
adverse events resolve. If dose-limiting safety or intolerability is determined, 
further dosing of a cohort may be stopped, and escalation discontinued. 
The PK plasma samples should be collected per Schedule of Events of the 
protocol. 
4.3.1 SCHEDULE OF EVENTS AND ASSESSMENTS 
Table 1 presents the schedule of study events and assessments. 
 


 
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Table 1: 
Schedule of Events 
 
Activity 
Pre-
Screening8  
Screening  
Pre-
Dose  
Treatment Evaluation Day 1 
Day 2 
Follow-
Up (+1)  
Day 3 
Discharge  
Day 7 
(+2)  
Time point  
Pre-
treatment 
Pre-
treatment  
-1 hr 
to 
time 
0  
5 
min 
10 
min 
15 
min 
30 
min  
1 
hr  
2 
hr  
4 
hr  
6 
hr  
8 
hr  
24 hr  
  
End of 
Study  
(-9/+12 
hr)  
Informed Consent  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History  
X 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics  
X 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight  
X 
  
  
  
  
  
  
  
  
  
  
  
X  
  
  
Height  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Mini-Mental State exam  
X 
  
  
  
  
  
  
  
  
 
  
  
X  
  
  
Clinical Dementia Rating 
Score 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Physical Exam  
X 
X  
  
  
  
  
  
  
  
  
  
  
X  
  
  
Safety Labs3  
X 
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
UTI and pregnancy  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
ECG with rhythm strip 7  
X 
  
X 
  
  
 
 
 
X 
 
 
 
X 
 
  
Pulse oximetry 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Resting vital signs2  
X 
X  
X  
  
  
 
X 
X 
X 
X 
X 
X 
X 
 
  
Orthostatic vital signs2  
X 
X  
X  
  
  
 
X 
X 
X 
X 
 
X 
X 
 
  
Inclusion/Exclusion criteria  
X 
X  
X  
  
  
 
 
 
 
 
 
 
 
 
  
Randomization  
  
  
X  
  
  
 
 
 
 
 
 
 
 
 
  
CMAI  
  
X  
X  
  
  
 
 
 
X 
 
 
 
 
 
X  
Study drug administration6  
  
  
X  
  
  
 
 
 
 
 
 
 
 
 
  
PAS  
X 
X  
X  
  
  
 
X 
X 
X 
X 
 
X 
X 
X 
X  
PEC  
X 
  
X  
  
  
 
X 
X 
X 
X 
 
X 
X 
X 
X  
ACES 
 
 
X 
 
 
 
 
X 
X 
X 
 
X 
 
 
 
CGI-Severity Agitation  
  
  
X  
  
  
 
 
 
X 
 
 
 
X 
 
  
CGI-Improvement/Change 
in Agitation  
  
  
  
  
  
 
X 
X 
X 
X 
 
X 
 
 
  


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C-SSRS  
X 
X  
  
  
  
 
 
 
 
 
 
 
X 
 
  
Buccal (SL) assessment 5   
  
  
  
X 
X 
X 
X 
 
X 
X 
 
 
X 
 
  
PK Sampling4  
  
  
  
  
  
 
X 
X 
X* 
X 
 
X 
X 
 
  
Concomitant Meds  
 X 
X  
X  
 X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Adverse Events  
X 
X  
X  
 X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
CCI


 
 
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4.4 TREATMENT 
Evaluation of three (3) doses of BXCL501 30 µg, 60 µg and 90 µg are planned, 
with an option to test different doses based on tolerability and safety. This is an 
adaptive design as doses selected for testing may be different from these, based 
upon safety reviews. Doses lower or higher may be chosen to test, and repeated, 
up to 180 µg within each cohort.  
Dosing may be repeated in the case of persistent or recurrent agitation, if there is 
no significant improvement (CGI-I of 1 or 2 as ‘very much’ or ‘much improved’) 
and no safety events evident. Dosing may be repeated up to a total of two repeat 
doses (at the same randomization group Active:Placebo) for all cohorts except 
for 90 µg dose which can only be repeated once (total 180 µg) if necessary, at 2 
hours post first dose but only after the 2-hour assessments are conducted and 
only within 12 hours post first dose.  Patients can only be re-dosed if they are 
hemodynamically stable, not hypotensive (must be greater than 90/60 
diastolic/systolic) and not bradycardic (must be greater than 60 bpm). Patients 
also cannot be re-dosed if they are orthostatic (a drop of 20 points in either SBP 
or DBP) or if they are experiencing an AE. 
4.5 RANDOMIZATION 
Upon confirmation of eligibility, subjects will be randomized to BXCL501 or 
placebo film. In each of the three-dose cohorts, 10 participants (8 drug treated, 2 
placebo) will be randomized 4:1 BXCL501 film: Placebo. Study randomization will 
be computer generated. 
5 
OUTCOME VARIABLE DEFINITIONS 
5.1 PRE-SCREENING, SCREENING, AND BASELINE CHARACTERISTICS 
Pre-Screening: Inclusion/exclusion criteria, demographic characteristics of age, 
sex, race, ethnicity, height, weight and body mass index (BMI), medical history, 
prior and concomitant medications, physical examination, resting and orthostatic 
vital signs, 12-lead electrocardiogram (ECG), clinical laboratory results, urine 
drug screen, Mini-Mental State Exam (MMSE), Clinical Dementia Rating (CDR), 
PAS, PEC, Columbia-Suicide Severity Rating Scale (C-SSRS), and any adverse 
events will be collected at pre-screening. 
 
Screening: Inclusion/exclusion criteria, demographic characteristics of age, sex, 
race, ethnicity, height, weight and body mass index (BMI), medical history, prior 
and concomitant medications, physical examination, resting and orthostatic vital 
signs, UTI screening, pregnancy test, PAS, C-SSRS, and any adverse events will 
be collected at screening. 
 
Baseline (Pre-Dose): Inclusion/exclusion criteria, resting and orthostatic vital 
signs, 12-lead ECG, concomitant medications, CMAI, PAS, PEC, ACES, CGI-S, 
and adverse events will be collected prior to dose administration. 


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5.2 EFFICACY ASSESSMENTS 
The effect of the study drug will be evaluated using several validated instruments 
as described below. 
5.2.1 PANSS-EXCITED COMPONENT (PEC) 
Assessment of drug effect on acute agitation will be done using the Positive and 
Negative Syndrome Scale – Excited Component (PEC). The PEC comprises 5 
items associated with agitation: poor impulse control, tension, hostility, 
uncooperativeness, and excitement; each scored 1 (minimum) to 7 (maximum). 
The PEC, the sum of these 5 subscales, thus ranges from 5 to 35. 
5.2.2 COHEN MANSFIELD AGITATION INVENTORY (CMAI) 
Assessment of drug effect on frequency of acute agitation will be also done using 
the CMAI. The CMAI is a rating questionnaire consisting of 29 behaviors each 
rated on a 7-point scale of frequency. It is possible that all 29 behaviors will not 
be relevant to a specific patient.  
The CMAI Instruction Manual (Cohen-Mansfield, 1989) acknowledges that the 
CMAI contains a diversified group of behaviors. The authors propose that 
researchers conduct their own factor analysis because factors depend on the 
population studied, and researchers need to conceptualize their understanding of 
these behaviors in order to aggregate the behaviors in a meaningful way. For 
these reasons, analysis of factors will be conducted after a determination of the 
appropriate items to include in each factor, based on the observed data from the 
study. Factors will most likely include physically aggressive behaviors, physically 
nonaggressive behaviors, verbally aggressive behaviors, and verbally 
nonaggressive behaviors. 
5.2.3 AGITATION-CALMNESS EVALUATION SCALE (ACES) 
The ACES is a single item measure rating overall agitation and sedation, where 1 
indicates marked agitation; 2 - moderate agitation; 3 - mild agitation; 4 - normal 
behavior; 5 - mild calmness; 6 - moderate calmness; 7 - marked calmness; 8 - 
deep sleep; and 9 – unarousable. 
5.2.4 PITTSBURG AGITATION SCALE (PAS) 
The Pittsburg Agitation Scale (PAS) is an instrument based on direct 
observations of the patient that is developed to monitor the severity of agitation 
associated with dementia.  There are four Behavior Groups observed (using a 0 
to 4-point scale) in the patient, Aberrant Vocalization, Motor Agitation, 
Aggressiveness, Resting Care. 
5.2.5 CGI-S AND CGI-I FOR AGITATION 
Both CGI-I and CGI-S will be focused on the severity of agitation rather than the 
severity of the overall illness of dementia.  


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Clinical Global Impression of Severity (CGI-S) will be rated based upon the 
severity of agitation at screening and Pre-dose (immediately prior to start of 
dosing). 
Severity of agitation will be assessed based on following scale: 
0 = Not assessed 
1 = Normal not at all symptomatic 
2 = Minimally symptomatic- few or mild symptoms -little interference with 
patients functioning 
3 = Mildly symptomatic-low level of symptoms-little interference in social 
functioning 
4 = Moderately symptomatic-some prominent symptoms-some 
interference in functioning 
5 = Markedly symptomatic-significant symptoms with very substantial 
interference in functioning 
6 = Severely symptomatic- very marked symptoms make it difficult for 
patients to engage with others  
7 = Among the most extremely symptomatic subjects-extreme symptoms -
patient is incapacitated or highly dangerous to self or others requires extra 
care and supervision 
Drug response on agitation will be evaluated by the Clinical Global Impressions – 
Improvement (CGI-I) which is performed after dosing and evaluated relative to 
Pre-dose baseline agitation.   
The CGI-I scores range from 1 to 7: 
0=not assessed (missing), 
1=very much improved, 
2=much improved, 
3=minimally improved, 
4=no change, 
5=minimally worse, 
6=much worse, 
7=very much worse 
5.3 SAFETY AND TOLERABILITY ASSESSMENTS 
Safety will be assessed during the study by the monitoring and recording of AEs, 
clinical laboratory test results (hematology, biochemistry, and urinalysis), vital 
sign measurements (systolic and diastolic blood pressures, heart rate measured 


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as pulse, respiratory rate, and temperature), ECG, and physical examination 
findings.  
5.3.1 ADVERSE EVENTS 
An adverse event (AE) is defined as any untoward medical occurrence in a 
subject or clinical investigation patient administered a pharmaceutical product 
that does not necessarily have a causal relationship with the product. An AE can 
therefore be any unfavorable and unintended sign (including a new, clinically 
important abnormal laboratory finding), symptom, or disease temporally 
associated with the product, whether or not it is related to the product. 
5.3.2 COLUMBIA SUICIDE SEVERITY RATING SCALE 
The C-SSRS (Oquendo et al., 2003) is a suicidal ideation rating scale that 
identifies behaviors and thoughts that are associated with an increased risk of 
suicidal actions in the future. The C-SSRS Baseline/Screening version will be 
conducted at Pre-Screening. The C-SSRS Since Last Visit version will be 
conducted at Screening and 24 hours post dosing. 
5.3.3 LABORATORY SAFETY ASSESSMENTS 
Samples for the following laboratory tests will be collected at the time points 
specified in the Schedule of Events (Table 1). 
Hematology: 
Consists of complete blood count (hemoglobin, 
hematocrit, white blood cell count with differential, red 
blood cell count, and platelet count) 
Serum chemistry: 
Includes blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase 
(serum glutamic-oxaloacetic transaminase), alanine 
aminotransferase (serum glutamic pyruvic 
transaminase), glucose, albumin, and total protein 
Urinalysis: 
Includes pH, specific gravity, protein, glucose, 
ketones, bilirubin, blood, nitrites, leukocytes, 
urobilinogen, microscopic urine analysis if dipstick 
positive 
Urine pregnancy test: 
Conducted by local labs 
Urine Drug Screen: 
Cocaine, amphetamine, phencyclidine, 
benzodiazepines, marijuana. (Note: Marijuana positive 
is allowed provided subject is not moderately to 
severely dependent, benzodiazepine positive are 
allowed if prescribed)  
5.3.4 VITAL SIGNS 
Resting vital signs, including systolic, diastolic blood pressure and heart rate 
(measured as pulse) will be measured after the subject has been in a recumbent 


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position for at least 5 minutes at the time points specified in the schedule of 
events. Measurements should be made at least 1 minute apart using the same 
arm at each visit. 
At indicated time points orthostatic measurement of systolic, diastolic blood 
pressure and heart rate will be measured after the subject has been standing for 
a total of 5 minutes. Temperature and respiratory rate will be recorded when 
orthostatic measurement is indicated in the schedule of events and are not 
required to be measured at resting vital sign time points.  
If the first measurement of vital signs (SBP, DBP and pulse) shows the following, 
vital signs will be measured again in triplicate (same arm, separated by at least 1 
minute) for: 
• Systolic Blood Pressure <90 mmHg 
• Diastolic Blood Pressure <60 mmHg 
• Pulse < 60 bpm 
5.3.5 ELECTROCARDIOGRAM 
A 12-lead ECG with rhythm strip will be performed at Pre-Screening, Pre-Dose, 
and 2 and 24 hours post-dose.  
5.3.6 PHYSICAL EXAMINATION 
A standard physical examination will be performed at Pre-Screening, Screening 
and 24 hours post dose.  The examination will include assessment of skin, head, 
ears, eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, 
lymph nodes, and musculoskeletal system/extremities.  Interim physical 
examinations will be performed at the investigator’s discretion if necessary, to 
evaluate AEs or clinical laboratory abnormalities. 
Height and weight will be measured at Screening and weight will be measured 
again at the Day 2 follow-up visit. 
5.3.7 BUCCAL ASSESSMENTS 
Buccal (SL) exam for local irritation and time to disappearance of the film will be 
performed by unblinded staff at 5, 10, 15, 30 min, 2 hr, 4 hr and 24 hr post first 
dose.   
5.4 CLINICAL DIAGNOSIS AND DESCRIPTION OF DEMENTIA 
The subtype of dementia will be determined and recorded based upon clinical 
neurologic and psychiatric evaluation to include review of all available medical 
information, medical records, documentation of prior evaluations, 
family/caretaker interviews, records, laboratory, genetics or other biomarkers, 
and results of neuroimaging (if available).  


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The following scales will characterize subject’s dementia (DSM-5 Major 
Neurocognitive disorder) in terms of cognitive and functional impairment. Both 
assessments will occur at the Pre-Screening and Day 2/Follow-Up visits. 
5.4.1 MMSE 
The Folstein Mini-Mental State Examination (MMSE) is an exam that tests an 
elderly person's cognitive ability. Domains measured by the MMSE include 
orientation to time and place, registration, attention and calculation, recall, 
naming, repetition, comprehension, reading, writing, and drawing.  Total points 
on this test is 30. Any score of 24 or more (out of 30) indicates a normal 
cognition. Below this, scores can indicate severe (≤9 points), moderate (10–18 
points) or mild (19–23 points) cognitive impairment. 
5.4.2 CDR  
The CDR® (Alzheimer's Disease Research Center, Washington University, St 
Louis) is a 5-point scale used to characterize six domains of cognitive and 
functional performance applicable to Alzheimer Disease and related dementias: 
memory, orientation, judgment & problem solving, community affairs, home & 
hobbies, and personal care. A score of 0 connotes no cognitive impairment, and 
then the remaining four points are for various stages of dementia where: 
 CDR-0 = normal 
 CDR-0.5 = very mild dementia 
 CDR-1 = mild 
 CDR-2 = moderate 
 CDR-3 = severe 
5.5 PHARMACOKINETICS 
For each subject, up to 6 blood samples (24 mL of blood) will be collected during 
the study for PK analysis. Blood samples (4 ml) will be collected at 0.5, 1, 2, 4, 8, 
and 24 hours post-dose per Table 1 Schedule of Events. A sample may not be 
collected if the physician in charge of the patient indicates in the source 
documents that the patient is in a mental state that is not conducive to PK 
sample collection and record the PEC score at the time of proposed sample 
collection.  
For re-dosed subjects only: An extra PK blood sample (4 ml) will be collected at 
2.5 hours post second dose in addition to the other times, totaling approximately 
73 ml. All PK sampling will occur only after the all other assessments at that time 
point are conducted. 
5.6 CONCOMITANT MEDICATIONS 
Concomitant medications will be reviewed and documented each day during the 
study. 


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6 
STUDY ENDPOINTS 
6.1 PRIMARY ENDPOINTS 
6.1.1 PRIMARY EFFICACY ENDPOINT 
• Change in PEC total score from baseline  
6.1.2 PRIMARY EFFICACY TIME POINT 
• 2 hours post-dose 
6.1.3 PRIMARY SAFETY AND TOLERABILITY ENDPOINTS 
• Comparison of cardiovascular parameters (BP, HR, pulse oximetry, ECG) 
between BXCL501 30 µg, 60 µg, and 90 µg and placebo 
6.2 SECONDARY ENDPOINTS 
6.2.1 SECONDARY EFFICACY ENDPOINTS 
• Change in PEC total score from baseline at 30 min, 1 hr, 4 hr, and 8 hr 
post-dose, and at Day 2, Day 3, and Day 7  
• Percentages of subjects at each dose who achieve a 40% reduction from 
baseline in PEC total score at 2 hr post-dose (“Responders”) 
• Change in PAS total score from baseline at 30 min, 1 hr, 2 hr, 4 hr, and 8 
hr post-dose, and at Day 2, Day 3, and Day 7 
• Change in ACES score from baseline at 1 hr, 2 hr, 4 hr, and 8 hr post-
dose 
• Change in CGI-S agitation score from baseline at 2 hr post-dose and at 
Day 2 
• CGI-I agitation score at 30 min, 1 hr, 2 hr 4 hr, and 8 hr post-dose  
• Change in CMAI total score from baseline at 2 hr post-dose and Day 7 
6.2.2 SECONDARY SAFETY AND TOLERABILITY ENDPOINTS 
• Time taken for medication to dissolve (1-30 sec, 31-59 sec, 1-2 min, 3+ 
min) – only assessed at 30 minutes 
• Negative reaction to the sublingual film in the examiner’s opinion (Yes/No) 
– assessed at 30 min, 2 hr, 4 hr, and 24 hr post-dose 
6.2.3 SECONDARY PHARMACOKINETIC ENDPOINTS 
A separate SAP for the PK analyses will be prepared for the study and will be 
finalized prior to database lock.  
6.3 EXPLORATORY ENDPOINTS 
• 
  
 
CCI


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7 
STATISTICAL ANALYSES 
Statistical analyses will be performed using SAS® software version 9.4. 
7.1 STATISTICAL METHODOLOGY 
7.1.1 SAMPLE SIZE DETERMINATION 
 
 
 
 
  
7.1.2 POPULATIONS FOR STATISTICAL ANALYSIS 
The following are analysis populations for the study: 
• Safety Population: All subjects who receive study drug 
• Intent to treat (ITT) Population: All subjects in the Safety Population who 
have a baseline and at least one post-baseline efficacy assessment 
• Per Protocol (PP) Population: All subjects in the ITT Population with no major 
protocol deviations. PP analyses may not be conducted if there are not 
sufficient protocol deviations deemed to impact analysis   
7.1.3 STATISTICAL ANALYSES – GENERAL CONSIDERATIONS 
Continuous variables will be summarized by treatment using descriptive statistics 
(n, mean, median, standard deviation, minimum, and maximum). The same 
number of decimal places as in the raw data will be presented when reporting 
minimum and maximum. One more decimal place than in the raw data will be 
presented when reporting mean and standard deviation. 
For categorical variables, frequencies and percentages will be presented by 
treatment.  
Baseline is defined as the last non-missing observation prior to initiation of study 
medication.  
All statistical testing will be based on a two-sided significance level of 0.05 unless 
otherwise stated.  
Listings for Appendix 16.2 in the CSR will include all the subject data points 
being collected or derived for analyses. Data listings will be provided for all 
subjects up to the point of withdrawal. 
7.1.4 PROCEDURES FOR HANDLING MISSING DATA 
No imputation will be performed for missing data unless stated otherwise. 
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For longitudinal analyses of continuous data, the Mixed Model Repeated 
Measures is considered valid under a Missing at Random (MAR) missingness 
mechanism.  
7.1.5 INTERIM ANALYSES 
 Due to an unanticipated delay in enrollment and study pause associated with the 
COVID-19 pandemic, we are planning on conducting a unblinded analysis to gain 
further experience with the endpoints under consideration and for decision 
making, including with respect to this study. The following data are planned to be 
included:  
 
Efficacy: 
 
T14.2.1.1_I Change from Baseline in PEC Score 
ITT 
T14.2.2.1_I Change from Baseline in PAS Score 
ITT 
T14.2.2.2_I Change from Baseline in ACES Score 
ITT 
T14.2.2.3_I Change from Baseline in CMAI Score 
ITT 
T14.2.2.4_I Change from Baseline in CGI-S Agitation Score 
ITT 
T14.2.3.1_I Change from Baseline in CMAI Factor Scores 
ITT 
 
Safety: 
 
L16.2.8_I 
Adverse Events 
SP 
L16.2.10_I 
Vital Signs 
SP 
L16.2.11.1_I 
Electrocardiogram Results 
SP 
L16.2.12_I 
Pulse Oximetry 
SP 
 
The intention of the safety analyses is primarily to evaluate the safety data 
collected in this elderly population. It is likely that this elderly frail population 
maybe more susceptible to the cardiovascular effects of BXCL501. The 
evaluation of these safety data will help us to plan the appropriate doses and or 
cohorts for this study population. In addition, many of the tools employed in this 
study to assess the effects of BXCL501 on agitation in this population, though 
widely used in chronic, longer studies, are yet to be fully characterized in a 
shortened study of this nature. Data from these tools will guide us to the 
appropriate use of these instruments as we move forward and enable us to 
choose the most relevant assessments in this study context 
7.2 SCREENING AND BASELINE CHARACTERISTICS 
Summary tables will be constructed by treatment for the Safety Population for the 
following Pre-Screening, Screening or Pre-Dose data: demographic 
characteristics of age, sex, race, ethnicity, weight, height and body mass index 
(BMI) (Table 14.1.3 in Appendix 14 of the CSR), medical history (Table 14.1.4), 


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prior medications (Table 14.1.5.1), laboratory examinations (Tables 14.3.5.1-
14.3.5.3), vital signs (Table 14.3.6), and ECG (Tables 14.3.7.1-14.3.7.2). 
Listings will be provided for eligibility criteria violations, demographics, and 
medical history (Listings 16.2.2-16.2.4). 
7.3 SUBJECT DISPOSITION  
Subject disposition will include the number of subjects who enroll in the study 
and the number and percentage of subjects included in each analysis population 
by treatment (Table 14.1.1). The frequency and percentage of subjects who 
withdraw or discontinue from the study, along with the reason for withdrawal or 
discontinuation, will be summarized by treatment (Table 14.1.2). Subject-level 
listings will be provided (Listings 16.2.1.1-16.2.1.2). 
All reported major protocol deviations and determined exclusions from any 
analysis population(s) will be documented and included in the CSR. 
7.4 STUDY TREATMENT ADMINISTRATION 
Study drug administration data will be listed by subject (Listing 16.2.5.2). 
7.5 EFFICACY ANALYSES 
The efficacy analyses described in this section compare each dose group to the 
pooled placebo group. Nominal significance levels will be reported with no 
adjustment for multiple tests.  
The intent to treat population will be analyzed and consist of all patients who take 
any study medication and who had both baseline and at least one efficacy 
assessment after dosing. Observations recorded after use of rescue medication 
will be censored (considered missing). 
7.5.1 PRIMARY EFFICACY ANALYSIS 
The primary efficacy endpoint is change from baseline in PEC total score. The 
primary efficacy time point will be at 2 hr post-dose.  
Placebo subjects will be pooled and contrasted with each dose. 
 
A mixed model for repeated measures (MMRM) will be used to assess treatment 
group differences for change from baseline. Change from baseline scores will 
include all available time points in a single model; the 2 hr time point is 
considered primary, and all other time points are considered secondary. Fixed 
effects will include treatment group, analysis visit, treatment-by-visit interaction, 
and a baseline-by-visit interaction. Visit will be fit as a repeated effect in the 
model using the repeated statement in SAS. The baseline score will be included 
as a continuous covariate. An unstructured covariance structure and Kenward-
Roger degrees of freedom will be used. In the event an unstructured covariance 
structure fails to converge, a Toeplitz structure will be used.  


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Least squares (LS) means will be presented for treatment and treatment*visit, 
with the significance level of the treatment-by-visit interaction presented in 
summary tables. Pair-wise comparisons of differences in LS means, two-sided 
95% confidence intervals (CIs) on differences, and p-values will be provided for 
each active treatment versus placebo for each visit and for treatment main 
effects (Tables 14.2.1.1-14.2.1.2, ITT and PP populations). Line graphs will be 
provided reflecting changes from baseline over time (Figures 14.2.1.1-14.2.1.2, 
ITT and PP populations). 
Individual patient scores for the PEC for all time points will be provided in a listing 
(Listing 16.2.6.1). 
7.5.2 SECONDARY EFFICACY ANALYSES 
All efficacy assessments will be summarized at all available time points over the 
course of the study. Secondary endpoint comparisons against baseline for all 
PEC time points will be included in the MMRM for the primary analysis, as 
described above. Findings from pairwise LS means will be used to differentiate 
primary versus secondary endpoints. Changes from baseline for PAS, ACES, 
CGI-S agitation score, and CMAI total score for all available time points will be 
analyzed using MMRM, using the specifications described above (Tables 
14.2.2.1-14.2.2.4). CGI-I agitation score will be compared between treatment and 
placebo groups using MMRM, however as there is no baseline measurement, it 
will not be included in the model (Table 14.2.2.5). Listings will be provided for 
individual patient scores (Listings 16.2.6.2-16.2.6.5). Line graphs will be provided 
reflecting changes from baseline over time in PAS score (Figures 14.2.2.1.1-
14.2.2.1.2, ITT and PP populations). 
Responder (ie, percentage change from baseline in the PEC score at 2 hours 
>40%) comparisons will be made via Fisher’s Exact test. Nominal p-values and 
the treatment difference and associated two-sided 95% confidence interval will 
be based on the Wald method with continuity correction and reported for each 
pairwise comparison of BXCL501 and placebo (Table 14.2.2.6). A bar chart will 
be provided reflecting percentages of responders at each time point for the 3 
treatment groups and placebo (Figures 14.2.2.1.2-14.2.2.1.2).  
For the CGI-S and CGI-I, scores of 0 (not assessed) will be set to missing prior to 
analysis. 
7.5.3 EXPLORATORY EFFICACY ANALYSES 
 
 
 
 
 
 
 
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7.6 SAFETY ANALYSES 
All safety analyses will be based on the Safety Population. Safety and tolerability 
will be assessed by clinical review of all safety parameters including AEs, 
laboratory values and vital signs. The safety analyses will include all results 
collected from randomization through the end of the study. 
7.6.1 PRIMARY SAFETY ANALYSES 
Comparison of cardiovascular parameters (BP, HR) between BXCL501 30 µg, 60 
µg, and 90 µg and placebo (Table 14.3.1).  
7.6.2 SECONDARY SAFETY ANALYSES 
A frequency summary will be presented for time taken for medication to dissolve 
at 30 minutes (1-30 seconds, 31-59 seconds, 1-2 minutes, 3+ minutes) and for 
negative reaction to sublingual film (Yes/No) assessed at 30 min, 2 hr, 4 hr, and 
24 hr post-dose. These parameters will be presented for each treatment group at 
each time point (Tables 14.3.2.1-14.3.2.2). Listings will include subject-level 
findings as well as all physical findings noted during buccal examinations 
(Listings 16.2.7.1-16.2.7.2).  
7.6.3 ADVERSE EVENTS 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Affairs (MedDRA version 22.0) coding system and summarized by system organ 
class and preferred term. Clinically significant deteriorations in physical 
examination findings will be reported and summarized as adverse events.  
Abnormal, clinically significant laboratory values will be reported and summarized 
as adverse events. 
New conditions detected or diagnosed after study intervention administration 
meet the definition of an AE even though they may have been present before 
the start of the study.  
 
The number and percentage of patients who report AEs will be summarized by 
system organ class and preferred term. Adverse events will also be summarized 
by severity as well as relationship to Study Medication. For summaries by 
relationship, relationship will be categorized as related (unlikely, possibly, 
probably, and definitely related) or not related.  
Patients who report the same preferred term on multiple occasions will be 
counted once for the preferred term: under the highest severity when 
summarized by severity and under the closest relationship to Study Medication 
when summarized by relationship.  If a patient reports multiple preferred terms 
for a system organ class, the patient will be counted only once for that system 
organ class. 


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Proportions for adverse events that are gender-specific (e.g., dysmenorrhea) will 
be based on the number of patients from that gender. 
The number and percentage of patients who experience AEs will be summarized 
by treatment group for the following: 
• By system organ class and preferred term (Table 14.3.3.1) 
• By severity, system organ class, and preferred term (Table 14.3.3.2) 
• By relationship to Study Medication (related, not related), system organ 
class, and preferred term (Table 14.3.3.3) 
• Serious adverse events by system organ class and preferred term (Table 
14.3.3.4) 
• Serious adverse events by relationship to Study Medication, system organ 
class, and preferred term (Table 14.3.3.5) 
• Adverse events resulting in discontinuation of Study Medication by system 
organ class and preferred term (Table 14.3.3.6) 
By-patient listings will be provided for any deaths, serious adverse events, and 
adverse events leading to discontinuation of treatment (Listing 16.2.8).  
7.6.4 COLUMBIA SUICIDE SEVERITY RATING SCALE 
The C-SSRS data will be summarized descriptively. Individual patient data will be 
provided in a listing (Listing 16.2.16). Only the following specific suicidal ideation 
and behavior category questions with any “Yes” responses will be summarized in 
a frequency distribution table at each post-randomization visit (Table 14.3.4): 
• Any Suicidal Ideation Category: 
o Wish to be Dead 
o Non-Specific Active Suicidal Thoughts 
o Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act 
o Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
o Active Suicidal Ideation with Specific Plan and Intent 
• Any Suicidal Behavior Category: 
o Completed Suicide 
o Non-Fatal Suicide Attempt 
o Interrupted Attempt 
o Aborted Attempt 
o Preparatory Acts or Behavior 


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o Any Suicidal Ideation or Behavior Category 
7.6.5 CLINICAL LABORATORY EVALUATIONS 
Each laboratory value and change from baseline (when appropriate) will be 
summarized for hematology, blood chemistry and urinalysis for each treatment 
and all available time points (Tables 14.3.5.1-14.3.5.3). Individual patient listings 
will be provided (Listing 16.2.9). 
7.6.6 PULSE OXIMETRY 
A listing of findings from pulse oximetry will be provided by subject (Listing 
16.2.12). 
7.6.7 PHYSICAL EXAMINATION 
A listing of abnormal physical examination findings will be provided by subject 
(Listing 16.2.13). Pregnancy, alcohol screening, and drug testing results will be 
provided by patient (Listing 16.2.14). 
7.6.8 CLINICAL DIAGNOSIS AND DESCRIPTION OF DEMENTIA 
MMSE and CDR scores will be listed by patient (Listings 16.2.15.1-16.2.15.2). 
7.6.9 VITAL SIGNS 
Vital signs will be summarized at each time point for each treatment group, using 
descriptive statistics. For any vital signs measured in triplicate, only the 2nd 
measurement will be included in the descriptive statistics. Change from baseline 
in vital signs values will also be summarized (Table 14.3.6). Individual patient 
listings will be provided (Listing 16.2.10). 
Baseline will be defined as the last vital sign value obtained before the first dose 
of Study Medication on Day 1.  
7.6.10 12-LEAD ELECTROCARDIOGRAM 
The change from baseline in ECG intervals (PR, QT, QTcF, QRS, and RR) to 
each scheduled assessment will be summarized descriptively by treatment 
group.   
Frequency distributions of the QTcF interval will be displayed by treatment group 
for abnormally high values that are greater than their baseline value at any post-
baseline visit and the following data cuts: 
>450 msec and > Baseline value 
>470 msec and > Baseline value 
>500 msec and > Baseline value 
 


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Additionally, the change from baseline frequency distributions of the QTcF 
interval will displayed by treatment group for the following data cuts: 
>30 msec increase 
>60 msec increase 
 
 (Tables 14.3.7.1-14.3.7.2 and Listings 16.2.11.1-16.2.11.2) 
7.6.11 CONCOMITANT MEDICATIONS 
Concomitant medications will be summarized (n and %) by ATC class and 
preferred term (coded by WHO Drug coding dictionary March 2019) for each 
treatment group (Table 14.1.5.2). Concomitant medications for individual patients 
will be provided in a listing (Listing 16.2.5.1). 
7.6.12 STUDY MEDICATION COMPLIANCE 
Study Medication compliance will be measured by the number of days of Study 
Medication administered and the percentage of scheduled doses that were 
taken. Descriptive statistics will be used to summarize dosing compliance within 
each treatment group (Table 14.1.6), as well as provided in a listing per patient 
(Listing 16.2.5.3). The number and percentage of subjects who have been re-
dosed for each treatment group, as well as the number of times each subject was 
re-dosed, will be summarized using descriptive statistics (Table 14.1.6). A listing 
of subjects who have been re-dosed, the number of times each subject was re-
dosed, and the times of re-dose will be provided (Listing 16.2.5.3). 
7.7 PHARMACOKINETIC and PHARMACODYNAMIC ANALYSIS 
A separate SAP for the PK and PK/PD analyses will be prepared for the study 
and will be finalized prior to database lock. Data from subjects who participated 
in the study will be included in the pharmacokinetic analysis. Subjects with 
missing sample concentrations will be included in the pharmacokinetic analyses 
provided their pharmacokinetic parameters can be adequately characterized 
based upon the remaining data. 
Deviation from procedures described in this protocol that impact the quality of 
data required to meet the objectives of the study will be documented and may 
result in exclusion of pharmacokinetic data from the analyses for a subject. This 
includes any deviations or events that would invalidate the evaluation of the 
pharmacokinetics. Examples of deviations and events which could result in 
exclusion of pharmacokinetic data from the analyses include emesis, 
immediately after dosing (within a predetermined time, to be specified in the SAP 
for PK and PK/PD analyses), sample processing or assay errors that lead to 
inaccurate bioanalytical results. Other deviations or events, which do not 
disqualify data from analyses, may require minor adjustments to calculations. If 
these occur, data analyses will be adjusted and documented accordingly such 
that conclusions are not biased. An example of such an event includes, but is not 


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limited to, minor deviations between the actual and scheduled time of sample 
collection. 
All pharmacokinetic parameters will be calculated using non-compartmental 
analysis using appropriate pharmacokinetic software. Actual sampling times will 
be used in all pharmacokinetic analyses. Per protocol times will be used to 
calculate mean plasma concentrations for graphical displays. 
Other PK analyses may be performed as appropriate. 
Pharmacodynamic data, including changes in blood pressure & heart rate, and 
changes in measures of agitation, from baseline may be evaluated as a function 
of time and as a function of measured or estimated plasma concentrations. 
Details will be described in the SAP for PK and PK/PD analyses. 
8 
REFERENCES 
Cohen-Mansfield J, Marx MS, & Rosenthal AS. (1989). A description of agitation 
in a nursing home. Journal of Gerontology: Medical Sciences, 44(3), M77-M84. 
Oquendo MA, Halberstam B, Mann JJ. Colombia Suicide Severity Rating Scale 
(C-SSRS) – Risk Factors for Suicidal Behavior: The Utility and Limitations of 
Research Instruments, in Standardized Evaluation in Clinical Practice. First MB, 
editor. American Psychiatric Publishing; Washington, DC: 2003: 103-131.  
 
 


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9 
TABLES, LISTINGS AND FIGURES 
9.1 TABLES 
The following tables are to be included in Appendix 14 of the CSR and may be 
modified with Sponsor’s approval. 
Table 
Title 
Population
T14.1.1 
Analysis Populations 
T14.1.2 
Subject Disposition 
SP 
T14.1.3 
Demographics 
SP 
T14.1.4 
Medical History 
SP 
T14.1.5.1 
Prior Medication 
SP 
T14.1.5.2 
Concomitant Medication 
SP 
T14.1.6 
Re-Dosed Subjects 
SP 
T14.2.1.1 
Change from Baseline in PEC Score 
ITT 
T14.2.1.2 
Change from Baseline in PEC Score 
PP 
T14.2.2.1 
Change from Baseline in PAS Score 
ITT 
T14.2.2.2 
Change from Baseline in ACES Score 
ITT 
T14.2.2.3 
Change from Baseline in CMAI Total Score 
ITT 
T14.2.2.4 
Change from Baseline in CGI-S Agitation Score 
ITT 
T14.2.2.5 
Differences in CGI-I Agitation Scores 
ITT 
T14.2.2.6 
Percentages of Responders in the PEC Score 
ITT 
T14.2.3.1 
 
ITT 
T14.2.3.2 
Differences in CMAI Factor Scores 
ITT 
T14.3.1 
Differences in Cardiovascular Parameters 
SP 
T14.3.2.1 
Differences in Time for Medication to Dissolve 
SP 
T14.3.2.2 
Differences in Buccal Assessment Findings 
SP 
T14.3.3.1 
Adverse Events by System Organ Class and Preferred 
Term 
SP 
T14.3.3.2 
Adverse Events by Severity, System Organ Class, and 
Preferred Term 
SP 
T14.3.3.3 
Adverse Events by Relationship to Study Medication, 
System Organ Class, and Preferred Term 
SP 
T14.3.3.4 
Serious Adverse Events by System Organ Class and 
Preferred Term 
SP 
T14.3.3.5 
Serious Adverse Events by Relationship to Study 
Medication, System Organ Class, and Preferred Term 
SP 
T14.3.3.6 
Adverse Events Leading to Discontinuation 
SP 
T14.3.4 
C-SSRS Suicidal Ideation or Behavior “Yes” Responses 
SP 
T14.3.5.1 
Summary of Hematology Measurements 
SP 
T14.3.5.2 
Summary of Serum Chemistry Measurements 
SP 
T14.3.5.3 
Summary of Urinalysis Measurements 
SP 
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Table 
Title 
Population
T14.3.6 
Summary of Vital Sign Measurements 
SP 
T14.3.7.1 
Changes in Electrocardiogram Measurements 
SP 
T14.3.7.2 
Frequency of Overall Electrocardiogram Results 
SP 
 
9.2 LISTINGS 
The following listings are to be included in the post-text Appendix 16 of the CSR 
and may be modified with Sponsor’s approval. 
Listing 
Title 
Population
L16.2.1.1 
Subject Disposition 
L16.2.1.2 
Analysis Populations 
L16.2.2 
Inclusion Criteria Not Met or Exclusion Criteria Met 
SP 
L16.2.3 
Demographics and Baseline Characteristics 
SP 
L16.2.4 
Medical History 
SP 
L16.2.5.1 
Concomitant Medications 
SP 
L16.2.5.2 
Study Drug Administration 
SP 
L16.2.5.3 
Re-Dosed Subjects 
SP 
L16.2.6.1 
PEC Assessment 
ITT 
L16.2.6.2 
PAS Assessment 
ITT 
L16.2.6.3 
ACES Assessment 
ITT 
L16.2.6.4 
CMAI Assessment 
ITT 
L16.2.6.5 
CGI-S and CGI-I Assessments 
ITT 
L16.2.7.1 
Time Taken for Medication to Dissolve 
SP 
L16.2.7.2 
Buccal Assessment for Local Irritation 
SP 
L16.2.8 
Adverse Events 
SP 
L16.2.9 
Clinical Laboratory Results 
SP 
L16.2.10 
Vital Signs 
SP 
L16.2.11.1 
Electrocardiogram Results 
SP 
L16.2.11.2 
Electrocardiogram Findings 
SP 
L16.2.12 
Pulse Oximetry 
SP 
L16.2.13 
Physical Examinations (Abnormal Findings) 
SP 
L16.2.14 
Drug and Pregnancy Screening Results 
SP 
L16.2.15.1 
MMSE Results 
SP 
L16.2.15.2 
CDR Results 
SP 
L16.2.16 
C-SSRS Results 
SP 
 
9.3 FIGURES 
The following figures are to be included in Appendix 14 of the CSR and may be 
modified with Sponsor’s approval. 


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F14.2.1.1 
Change from Baseline in PEC Score 
ITT 
F14.2.1.2 
Change from Baseline in PEC Score 
PP 
F14.2.2.1.1 Change from Baseline in PAS Score 
ITT 
F14.2.2.1.2 Change from Baseline in PAS Score 
PP 
F14.2.2.2.1 Percentages of Responders in the PEC Score 
ITT 
F14.2.2.2.2 Percentages of Responders in the PEC Score 
PP 
 


 
 
 
 
 
 
 
 
 
 
A PHASE Ib/II, MULTICENTER, RANDOMIZED, 
DOUBLE BLIND, PLACEBO CONTROLLED, 
ASCENDING DOSE FINDING, EFFICACY, 
PHARMACOKINETIC AND SAFETY STUDY OF 
BXCL501 IN AGITATION ASSOCIATED WITH 
DEMENTIA 
 
NCT04251910 
04/14/2021 


 
 
BioXcel Therapeutics, Inc. 
 
 
Protocol BXCL501-103 
 
 
 
Statistical Analysis Plan: Part B Final Version 1.0 April 14, 2021 
Page | 1 
 
STATISTICAL ANALYSIS PLAN: PART B 
 
PROTOCOL: BXCL501-103 
 
A Phase Ib/II, Multicenter, Randomized, Double Blind, 
Placebo Controlled, Ascending Dose Finding, Efficacy, 
Pharmacokinetic and Safety Study of BXCL501 in 
Agitation Associated with Dementia 
 
 
SPONSOR:  
BioXcel Therapeutics, Inc. 
555 Long Wharf Drive 
12th Floor 
New Haven, CT 06511 
 
 
PRODUCT:  
BXCL501 
 
 
AUTHOR: 
 
 
 
Lead Statistician 
Cognitive Research Corporation 
200 Central Ave. Suite 1230 
Saint Petersburg, Florida 33701 
 
 
DATE: 
 
14 April 2021 
 
 
STATUS: 
 
Final Version 1.0 
 
PPD
PPD




 
 
BioXcel Therapeutics, Inc. 
 
 
Protocol BXCL501-103 
 
 
 
Statistical Analysis Plan: Part B Final Version 1.0 April 14, 2021 
Page | 3 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................... 3 
AMENDMENT HISTORY ...................................................................................... 5 
1 LIST OF ABBREVIATIONS ............................................................................ 5 
2 INTRODUCTION ............................................................................................. 7 
3 STUDY OBJECTIVES ..................................................................................... 7 
3.1 PRIMARY OBJECTIVE ............................................................................................ 7 
3.2 SECONDARY OBJECTIVES ................................................................................... 7 
4 STUDY DESIGN .............................................................................................. 8 
4.1 DURATION OF STUDY ............................................................................................ 8 
4.2 NUMBER OF PARTICIPANTS (STUDY POPULATION) ......................................... 8 
4.3 DESIGN .................................................................................................................... 8 
4.3.1 
PRE-SCREENING AND SCREENING PERIOD ................................................................. 9 
4.3.2 
TREATMENT PERIOD ........................................................................................................ 9 
4.3.3 
FOLLOW-UP PERIOD ...................................................................................................... 10 
4.4 SCHEDULE OF EVENTS AND ASSESSMENTS .................................................. 10 
4.5 TREATMENT .......................................................................................................... 14 
4.6 RANDOMIZATION ................................................................................................. 14 
5 OUTCOME VARIABLE DEFINITIONS ......................................................... 14 
5.1 PRE-SCREENING, SCREENING, AND BASELINE CHARACTERISTICS ........... 14 
5.2 EFFICACY ASSESSMENTS .................................................................................. 14 
5.2.1 
PANSS-EXCITED COMPONENT (PEC) .......................................................................... 14 
5.2.2 
PANSS SUPPLEMENTAL ITEMS .................................................................................... 14 
5.2.3 
COHEN MANSFIELD AGITATION INVENTORY (CMAI) ................................................. 15 
5.2.4 
AGITATION-CALMNESS EVALUATION SCALE (ACES) ................................................ 15 
5.2.5 
PITTSBURG AGITATION SCALE (PAS) .......................................................................... 15 
5.2.6 
CGI-S AND CGI-I FOR AGITATION ................................................................................. 15 
5.3 SAFETY AND TOLERABILITY ASSESSMENTS ................................................... 16 
5.3.1 
ADVERSE EVENTS .......................................................................................................... 17 
5.3.2 
COLUMBIA SUICIDE SEVERITY RATING SCALE .......................................................... 17 
5.3.3 
LABORATORY SAFETY ASSESSMENTS ....................................................................... 17 
5.3.4 
VITAL SIGNS..................................................................................................................... 18 
5.3.5 
ELECTROCARDIOGRAM ................................................................................................. 18 
5.3.6 
PHYSICAL EXAMINATION ............................................................................................... 18 
5.3.7 
BUCCAL ASSESSMENTS ................................................................................................ 19 
5.4 CLINICAL DIAGNOSIS AND DESCRIPTION OF DEMENTIA ............................... 19 
5.4.1 
MMSE ................................................................................................................................ 19 
5.4.2 
CDR ................................................................................................................................... 19 
5.5 PHARMACOKINETICS .......................................................................................... 19 
5.6 CONCOMITANT MEDICATIONS ........................................................................... 20 
6 STUDY ENDPOINTS ..................................................................................... 20 
6.1 PRIMARY ENDPOINTS ......................................................................................... 20 
6.1.1 
PRIMARY EFFICACY ENDPOINT .................................................................................... 20 
6.1.2 
PRIMARY EFFICACY TIMEPOINT ................................................................................... 20 
6.1.3 
PRIMARY SAFETY AND TOLERABILITY ENDPOINTS .................................................. 20 


 
 
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6.2 SECONDARY ENDPOINTS ................................................................................... 20 
6.2.1 
SECONDARY EFFICACY ENDPOINTS ........................................................................... 20 
6.2.2 
SECONDARY SAFETY AND TOLERABILITY ENDPOINTS ........................................... 21 
6.2.3 
SECONDARY PHARMACOKINETIC ENDPOINTS.......................................................... 21 
6.3 EXPLORATORY ENDPOINTS ............................................................................... 21 
7 STATISTICAL ANALYSES ........................................................................... 21 
7.1 STATISTICAL METHODOLOGY ........................................................................... 21 
7.1.1 
SAMPLE SIZE DETERMINATION .................................................................................... 21 
7.1.2 
POPULATIONS FOR STATISTICAL ANALYSIS .............................................................. 21 
7.1.3 
STATISTICAL ANALYSES – GENERAL CONSIDERATIONS ......................................... 22 
7.1.4 
PROCEDURES FOR HANDLING MISSING DATA .......................................................... 22 
7.1.5 
INTERIM ANALYSES ........................................................................................................ 22 
7.2 SCREENING AND BASELINE CHARACTERISTICS ............................................ 22 
7.3 SUBJECT DISPOSITION ....................................................................................... 22 
7.4 STUDY TREATMENT ADMINISTRATION ............................................................. 23 
7.5 EFFICACY ANALYSES .......................................................................................... 23 
7.5.1 
PRIMARY EFFICACY ANALYSIS ..................................................................................... 23 
7.5.2 
SECONDARY EFFICACY ANALYSES ............................................................................. 24 
7.5.3 
EXPLORATORY EFFICACY ANALYSES ......................................................................... 24 
7.6 SAFETY ANALYSES .............................................................................................. 24 
7.6.1 
PRIMARY SAFETY ANALYSES ....................................................................................... 24 
7.6.2 
SECONDARY SAFETY ANALYSES ................................................................................. 24 
7.6.3 
ADVERSE EVENTS .......................................................................................................... 25 
7.6.4 
COLUMBIA SUICIDE SEVERITY RATING SCALE .......................................................... 26 
7.6.5 
CLINICAL LABORATORY EVALUATIONS ...................................................................... 26 
7.6.6 
PULSE OXIMETRY ........................................................................................................... 26 
7.6.7 
PHYSICAL EXAMINATION ............................................................................................... 26 
7.6.8 
CLINICAL DIAGNOSIS AND DESCRIPTION OF DEMENTIA ......................................... 26 
7.6.9 
VITAL SIGNS..................................................................................................................... 27 
7.6.10 
12-LEAD ELECTROCARDIOGRAM ............................................................................... 27 
7.6.11 
CONCOMITANT MEDICATIONS .................................................................................... 28 
7.6.12 
RESCUE MEDICATIONS ................................................................................................ 28 
7.6.13 
STUDY MEDICATION COMPLIANCE ............................................................................ 28 
7.7 PHARMACOKINETIC and PHARMACODYNAMIC ANALYSIS ............................. 28 
8 REFERENCES .............................................................................................. 29 
9 TABLES, LISTINGS AND FIGURES ............................................................ 30 
 


 
 
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AMENDMENT HISTORY 
Not applicable 
1 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACES 
Agitation-Calmness Evaluation Scale 
AE 
Adverse Event 
BMI 
Body Mass Index 
BP 
Blood pressure 
CDR 
Clinical Dementia Rating Scale 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression-Severity 
CMAI 
Cohen Mansfield Agitation Inventory 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
Diastolic blood pressure 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
HR 
Heart rate 
hr 
hour 
ITT 
Intent to Treat 
kg 
kilogram 
µg/µcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
Min 
Minutes 
mL 
milliliter 
mm 
millimeters 
mmHG 
millimeters of mercury 


 
 
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Abbreviation 
Definition 
MMRM 
Mixed model repeated measures 
MMSE 
Mini Mental Status Exam 
PANSS/PANSS-
EC 
Positive and Negative Syndrome Scale/ Positive and Negative 
Syndrome Scale – Excited Component 
PAS 
Pittsburgh Agitation Scale 
PEC 
Positive and Negative Syndrome Scale – Excited Component 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SL 
Sublingual  
SP 
Safety Population  
TFLs 
Tables, Figures, and Listings 
WHO 
World Health Organization 
 
 


 
 
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2 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses for 
Part B of the study entitled “A Phase Ib/II, Multicenter, Randomized, Double 
Blind, Placebo Controlled, Ascending Dose Finding, Efficacy, Pharmacokinetic 
and Safety Study of BXCL501 in Agitation Associated with Dementia” (V7, 04 
February 2021). All planned PK analyses will be specified in a separate 
document. Mock shells for Appendix 14 of the Clinical Study Report (CSR) will 
also be produced as a separate working document to facilitate programming of 
Tables, Figures, and Listings (TFLs) according to the finalized SAP. The SAP is 
to be interpreted in conjunction with the protocol, and supersedes the statistical 
considerations identified in the protocol. If the final clinical study report contains 
changes to any planned statistical analyses, the justification for any such 
differences will be fully documented in the clinical study report (CSR). 
3 
STUDY OBJECTIVES 
The objective of Part B is to test a dose of 40 µg as potentially the lowest safe 
dose that remains effective vs. placebo in reducing agitation. In addition, the data 
collected in Part B will be from a larger number of sites and raters which enables 
a more accurate estimate of variance for powering future Phase 3 development 
studies. 
3.1 PRIMARY OBJECTIVE 
Describe the safety and tolerability of 40 µg of BXCL501 for study of efficacy in 
treatment of acute agitation associated with dementia. 
3.2 SECONDARY OBJECTIVES 
Secondary objectives are as follows: 
 
• Describe the onset and magnitude of calming effects of 40 µg of BXCL501 
on symptoms of acute agitation associated with dementia compared to 
placebo. 
• Describe the duration of calming as measured by the Positive and 
Negative Syndrome Scale Excited Component (PEC) and the Agitation-
Calmness Evaluation Scale (ACES). 
• Describe the tolerability and safety profile of 40 µg of BXCL501, as 
determined by adverse events (AEs) and vital signs vs. placebo. 
• Describe clinical effects as measured by the Clinician Global Impression 
of Severity scale (CGI-S) to assess agitation and then Improvement (CGI-
I) after drug administration. 
• Describe the frequency of agitation using the Cohen Mansfield Agitation 
Inventory (CMAI) at baseline and 2 hours post-dose. 


 
 
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• Determine the approximate dissolution time of BXCL501 films in the 
sublingual space. 
• Assess the local tolerability via buccal examination after dosing BXCL501 
film. 
• Describe the PK and exposure of dexmedetomidine as delivered by 
sublingual BXCL501 dosing. 
• Part B: Describe the duration of calming as measured by the 3 
supplementary items of the PANSS. 
4 
STUDY DESIGN 
4.1 DURATION OF STUDY 
The total duration of the study, excluding Screening, will be approximately seven 
days (Day 1 through follow-up). The duration of study treatment 
(BXCL501/placebo) is one day. 
4.2 NUMBER OF PARTICIPANTS (STUDY POPULATION) 
In Part B a total of 46 subjects will be randomized 1:1 to receive BXCL501 40 µg 
or matching placebo film (23 subjects on BXCL501 and 23 on placebo). 
4.3 DESIGN 
Part A of this study is a randomized, double-blind, placebo-controlled, multiple 
ascending dose study assessing efficacy, PK, safety, and tolerability of BXCL501 
dosing in adult (65 years and older) males and females with acute agitation 
associated with dementia. See the SAP for Part A for more details on Part A 
study design. 
Part B is a parallel group study of 40 µg BXCL501 versus placebo. Forty-six 
patients in Part B of this study will be randomized in a 1:1 ratio to receive 
BXCL501 40 µg or matching placebo film. The study will take place at 
approximately 4 centers in the United States. 
Eligible patients (those with any type of dementia) may be identified in skilled 
nursing facilities, mental health, psychiatric or medical emergency services 
including medical/psychiatric observation units, or as newly admitted to a hospital 
setting for acute agitation or already in hospital for chronic underlying conditions. 
Subjects will remain in their facility while undergoing screening procedures to 
assess eligibility. 
Patients in Part B of this study will be seniors age 65 and above, who are semi-
independent, and able to carry out many of their activities of daily living under 
minimal supervision, such as those who reside in assisted living facilities. 


 
 
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The study will consist of a pre-screening/screening period, treatment period, and 
a follow-up period.  
Patients in Part B of this study will have assessments as outlined in the Schedule 
of Events (Table 1). The Pre-Screening visit may occur no more than 28 days 
before first dose of study treatment. 
4.3.1 PRE-SCREENING AND SCREENING PERIOD 
At the Pre-Screening visit, if a subject has orthostatic hypotension (OH) on more 
than 1 instance in the same day during the 1-week safety observation period, 
they will be excluded from study participation. Following the 1-week safety 
observation period, subjects will complete the Screening visit as outlined in the 
Schedule of Events (Table 1). 
4.3.2 TREATMENT PERIOD 
Upon confirmation of eligibility, Part B subjects will be randomized to receive a 
single dose of BXCL501 40 µg of or matching placebo film. 
Up to 1 hour prior to dosing, pre-dose vital signs, including BP, orthostatic BP, 
will be collected. If OH is observed or if SBP <110 mmHg, then the subject will be 
hydrated and dosing will be delayed until OH is resolved. Every effort will be 
made to keep the subject sitting or lying down for at least 2 hours after dosing. 
After pre-dose vitals have been collected, a single dose of BXCL501 or placebo 
film will be administered sublingually by the patient if able with instructions from 
an unblinded staff member who will not participate in evaluation of safety or 
efficacy. The drug film will be retained in the sublingual cavity until dissolved. 
Participants will also be evaluated for local irritation around the area where the 
film is placed. Efficacy and safety assessments will be conducted periodically 
before and after dosing.  
Vital signs and ECGs will be conducted at the timepoints indicated in the 
schedule of events. Participants will be allowed water as desired 15 minutes after 
completion of dosing. Safety and tolerability assessments will be continued until 
the morning of Day 3 and will be repeated on Day 7 + 2 days. Smoking will be 
permitted according to the site’s policies. After the 4 hour assessments are 
completed, at the discretion of the PI, rescue therapy may be initiated using 
standard of care treatment which may include lorazepam 0.5-5 mg po/IM or an 
antipsychotic medication po/IM. 
Any abnormal vital sign measurement, clinical laboratory test, physical 
examination finding, or ECG parameter deemed clinically significant by the 
investigator will be repeated, including test results obtained on the final study day 
or upon early termination. For any test abnormality deemed clinically significant, 
repeat analysis will be performed during the follow-up period and until the value 


 
 
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returns to baseline (or within normal limits) or the investigator deems the 
abnormality to be of no clinical significance. Subjects presenting with a clinically 
significant urinary tract infection (UTI) as determined by clinical laboratory tests 
will be excluded from the study. 
A nurse will be present prior to dosing and remain present for at least 6 hours 
after dosing or longer if needed, until any safety concerns, intolerability or 
adverse events resolve. 
The PK plasma samples should be collected per the Schedule of Events (Table 
1). 
4.3.3 FOLLOW-UP PERIOD 
The Follow-up Period will encompass the Day 2 Follow-Up and the Day 3 visits 
as detailed in Table 1. 
Subjects will also be required to undergo a Day 7 End of Study visit, in which the 
CMAI, PEC, and PAS, along with safety assessments, will be performed. 
4.4 SCHEDULE OF EVENTS AND ASSESSMENTS 
Table 1 presents the schedule of study events and assessments. 
 


 
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Table 1: 
Schedule of Events 
Activity 
Pre- 
Screening7,8 
Screening 
Pre- 
Dose1 
Treatment Evaluation Day 1 
Day 2 
Follow-Up 
(+1 day) 
Day 3 
Day 7 
(+2 
days) 
Time point 
Pre- 
treatment 
Pre- 
treatment 
-1 hr 
to 
time 0 
5 
min 
10 
min 
15 
min 
30 
min 
1 
hr 
2 
hr 
4 
hr 
6 
hr 
8 
hr 
24 hr 
End 
of 
Study 
(-9/+12 hr) 
Informed consent 
X 
Medical history 
X 
X 
Demographics 
X 
X 
Weight 
X 
X 
Height 
X 
Mini-Mental State exam 
X 
X 
Clinical Dementia Rating 
Score 
X 
X 
Physical exam 
X 
X 
X 
Safety laboratory 
assessments3 
X 
X 
X 
UDS9 
X 
X10 
UTI and pregnancy 
X 
ECG with rhythm strip6 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
Resting vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Orthostatic vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Activity 
Pre- 
Screening7,8 
Screening 
Pre- 
Dose1 
Treatment Evaluation Day 1 
Day 2 
Follow-Up 
(+1 day) 
Day 3 
Day 7 
(+2 
days) 
Time point 
Pre- 
treatment 
Pre- 
treatment 
-1 hr 
to 
time 0 
5 
min 
10 
min 
15 
min 
30 
min 
1 
hr 
2 
hr 
4 
hr 
6 
hr 
8 
hr 
24 hr 
End 
of 
Study 
(-9/+12 hr) 
Inclusion/Exclusion criteria 
X 
X 
X 
Randomization 
X 
CMAI 
X 
X 
X 
X 
Study drug administration 
X 
PAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PEC11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACES 
X 
X 
X 
X 
X 
CGI-Severity (agitation) 
X 
X 
X 
CGI-Improvement (change 
in agitation) 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
Buccal (SL) assessment5 
X 
X 
X 
X 
X 
X 
X 
PK sampling4 
X 
X 
X* 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CCI


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CCI


 
 
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4.5 TREATMENT 
Evaluation of a single dose of BXCL501 40 µg is planned for Part B.  
4.6 RANDOMIZATION 
Upon confirmation of eligibility, Part B subjects will be randomized to receive a 
single dose of BXCL501 40 µg of or matching placebo film. Study randomization 
will be computer generated. 
5 
OUTCOME VARIABLE DEFINITIONS 
5.1 PRE-SCREENING, SCREENING, AND BASELINE CHARACTERISTICS 
Pre-Screening: Inclusion/exclusion criteria, demographic characteristics of age, 
sex, race, ethnicity, height, weight and body mass index (BMI), medical history, 
prior and concomitant medications, physical examination, resting and orthostatic 
vital signs, 12-lead electrocardiogram (ECG), clinical laboratory results, urine 
drug screen, Mini-Mental State Exam (MMSE), Clinical Dementia Rating (CDR), 
PAS, PEC, Columbia-Suicide Severity Rating Scale (C-SSRS), and any adverse 
events will be collected at pre-screening. 
 
Screening: Inclusion/exclusion criteria, demographic characteristics of age, sex, 
race, ethnicity, height, weight and body mass index (BMI), medical history, prior 
and concomitant medications, physical examination, resting and orthostatic vital 
signs, UTI screening, pregnancy test, PAS, C-SSRS, and any adverse events will 
be collected at screening. 
 
Baseline (Pre-Dose): Inclusion/exclusion criteria, resting and orthostatic vital 
signs, 12-lead ECG, concomitant medications, CMAI, PAS, PEC, ACES, CGI-S, 
and adverse events will be collected prior to dose administration. 
5.2 EFFICACY ASSESSMENTS 
The effect of the study drug will be evaluated using several validated instruments 
as described below. 
5.2.1 PANSS-EXCITED COMPONENT (PEC) 
Assessment of drug effect on acute agitation will be done using the Positive and 
Negative Syndrome Scale – Excited Component (PEC). The PEC comprises 5 
items associated with agitation: poor impulse control, tension, hostility, 
uncooperativeness, and excitement; each scored 1 (minimum) to 7 (maximum). 
The PEC, the sum of these 5 subscales, thus ranges from 5 to 35. 
5.2.2 PANSS SUPPLEMENTAL ITEMS  
The PANSS Supplementary Items for the Aggression Risk Profile comprises 3 
items, each rated on a scale of 1 to 7, with 1 reflecting absence of the 
emotion/behavior and 7 reflecting extreme emotion/behavior. The specific items 


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reflect anger, difficulty in delaying gratification, and affective lability. The total 
score ranges from 3 to 21. This scale is not administered in Part A of the study.  
5.2.3 COHEN MANSFIELD AGITATION INVENTORY (CMAI) 
Assessment of drug effect on frequency of acute agitation will be also done using 
the CMAI. The CMAI is a rating questionnaire consisting of 29 behaviors each 
rated on a 7-point scale of frequency. It is possible that all 29 behaviors will not 
be relevant to a specific patient. Only behaviors manifest by the subject at 
baseline will be assessed throughout the study resulting in a modified CMAI. 
Behaviors which are present immediately pre-dose will be rated throughout the  
post-dose timepoints. At each timepoint after Pre-dose the rater will note that 
items (behaviors) which were not manifest prior to dosing have not emerged 
since last CMAI assessment. Should they emerge, these items shall be included 
in ratings.  
The CMAI Instruction Manual (Cohen-Mansfield, 1989) acknowledges that the 
CMAI contains a diversified group of behaviors. The authors propose that 
researchers conduct their own factor analysis because factors depend on the 
population studied, and researchers need to conceptualize their understanding of 
these behaviors in order to aggregate the behaviors in a meaningful way. For 
these reasons, analysis of factors may be conducted, should the data warrant the 
analysis. The factor analysis would include a determination of the appropriate 
items to include in each factor, based on the observed data from the study. 
Factors would most likely include physically aggressive behaviors, physically 
nonaggressive behaviors, verbally aggressive behaviors, and verbally 
nonaggressive behaviors. 
5.2.4 AGITATION-CALMNESS EVALUATION SCALE (ACES) 
The ACES is a single item measure rating overall agitation and sedation, where 1 
indicates marked agitation; 2 - moderate agitation; 3 - mild agitation; 4 - normal 
behavior; 5 - mild calmness; 6 - moderate calmness; 7 - marked calmness; 8 - 
deep sleep; and 9 – unarousable. 
5.2.5 PITTSBURG AGITATION SCALE (PAS) 
The Pittsburg Agitation Scale (PAS) is an instrument based on direct 
observations of the patient that is developed to monitor the severity of agitation 
associated with dementia.  There are four Behavior Groups observed (using a 0 
to 4-point scale) in the patient, Aberrant Vocalization, Motor Agitation, 
Aggressiveness, Resisting Care. 
5.2.6 CGI-S AND CGI-I FOR AGITATION 
Both CGI-I and CGI-S will be focused on the severity of agitation rather than the 
severity of the overall illness of dementia.  


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Clinical Global Impression of Severity (CGI-S) will be rated based upon the 
severity of agitation at screening and Pre-dose (immediately prior to start of 
dosing). 
Severity of agitation will be assessed based on following scale: 
0 = Not assessed 
1 = Normal not at all symptomatic 
2 = Minimally symptomatic- few or mild symptoms -little interference with 
patients functioning 
3 = Mildly symptomatic-low level of symptoms-little interference in social 
functioning 
4 = Moderately symptomatic-some prominent symptoms-some 
interference in functioning 
5 = Markedly symptomatic-significant symptoms with very substantial 
interference in functioning 
6 = Severely symptomatic- very marked symptoms make it difficult for 
patients to engage with others  
7 = Among the most extremely symptomatic subjects-extreme symptoms -
patient is incapacitated or highly dangerous to self or others requires extra 
care and supervision 
Drug response on agitation will be evaluated by the Clinical Global Impressions – 
Improvement (CGI-I) which is performed after dosing and evaluated relative to 
Pre-dose baseline agitation.   
The CGI-I scores range from 1 to 7: 
0=not assessed (missing), 
1=very much improved, 
2=much improved, 
3=minimally improved, 
4=no change, 
5=minimally worse, 
6=much worse, 
7=very much worse 
5.3 SAFETY AND TOLERABILITY ASSESSMENTS 
Safety will be assessed during the study by the monitoring and recording of AEs, 
clinical laboratory test results (hematology, biochemistry, and urinalysis), vital 
sign measurements (systolic and diastolic blood pressures, heart rate measured 


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as pulse, respiratory rate, and temperature), ECG, and physical examination 
findings.  
5.3.1 ADVERSE EVENTS 
An adverse event (AE) is defined as any untoward medical occurrence in a 
subject or clinical investigation patient administered a pharmaceutical product 
that does not necessarily have a causal relationship with the product. An AE can 
therefore be any unfavorable and unintended sign (including a new, clinically 
important abnormal laboratory finding), symptom, or disease temporally 
associated with the product, whether or not it is related to the product. 
 
New conditions detected or diagnosed after study intervention administration 
meet the definition of an AE even though they may have been present before 
the start of the study.  
 
Adverse events with an onset following exposure to study treatment (during the 
BXCL501 treatment phase) or AEs already present that worsen in intensity or 
frequency following exposure to study treatment are considered treatment 
emergent adverse events (TEAEs). 
5.3.2 COLUMBIA SUICIDE SEVERITY RATING SCALE 
The C-SSRS (Oquendo et al., 2003) is a suicidal ideation rating scale that 
identifies behaviors and thoughts that are associated with an increased risk of 
suicidal actions in the future. The C-SSRS Baseline/Screening version will be 
conducted at Pre-Screening. The C-SSRS Since Last Visit version will be 
conducted at Screening and 24 hours post dosing. 
5.3.3 LABORATORY SAFETY ASSESSMENTS 
Samples for the following laboratory tests will be collected at the timepoints 
specified in the Schedule of Events (Table 1). 
Hematology: 
Consists of complete blood count (hemoglobin, 
hematocrit, white blood cell count with differential, red 
blood cell count, and platelet count) 
Serum chemistry: 
Includes blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase 
(serum glutamic-oxaloacetic transaminase), alanine 
aminotransferase (serum glutamic pyruvic 
transaminase), glucose, albumin, and total protein 
Urinalysis: 
Includes pH, specific gravity, protein, glucose, 
ketones, bilirubin, blood, nitrites, leukocytes, 
urobilinogen, microscopic urine analysis if dipstick 
positive 
Urine pregnancy test: 
Conducted by local labs 


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Urine Drug Screen: 
Cocaine, amphetamine, phencyclidine, 
benzodiazepines, marijuana. (Note: Marijuana positive 
is allowed provided subject is not moderately to 
severely dependent, benzodiazepine positive are 
allowed if prescribed)  
5.3.4 VITAL SIGNS 
Resting vital signs, including systolic, diastolic blood pressure and heart rate 
(measured as pulse) will be measured after the subject has been in a recumbent 
position for at least 5 minutes at the timepoints specified in the schedule of 
events. Measurements should be made at least 1 minute apart using the same 
arm at each visit. 
At indicated timepoints orthostatic measurement of systolic, diastolic blood 
pressure and heart rate will be measured after the subject has been standing for 
a total of 5 minutes. Temperature and respiratory rate will be recorded when 
standing measurement is indicated in the schedule of events and are not 
required to be measured at resting vital sign timepoints.  
If the first measurement of vital signs (SBP, DBP and pulse) shows the following, 
vital signs will be measured again in triplicate (same arm, separated by at least 1 
minute) for: 
• Systolic Blood Pressure <90 mmHg 
• Diastolic Blood Pressure <60 mmHg 
• Pulse < 60 bpm 
5.3.5 ELECTROCARDIOGRAM 
A 12-lead ECG with rhythm strip will be performed at Pre-Screening, Pre-Dose, 
and 2 and 24 hours post-dose.  
5.3.6 PHYSICAL EXAMINATION 
A standard physical examination will be performed at Pre-Screening, Screening 
and 24 hours post dose.  The examination will include assessment of skin, head, 
ears, eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, 
lymph nodes, and musculoskeletal system/extremities.  Interim physical 
examinations will be performed at the investigator’s discretion if necessary, to 
evaluate AEs or clinical laboratory abnormalities. 
Height and weight will be measured at Screening and weight will be measured 
again at the Day 2 follow-up visit. 


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5.3.7 BUCCAL ASSESSMENTS 
Buccal (SL) exam for local irritation and time to disappearance of the film will be 
performed by unblinded staff at 5, 10, 15, 30 min, 2 hr, 4 hr and 24 hr post first 
dose.   
5.4 CLINICAL DIAGNOSIS AND DESCRIPTION OF DEMENTIA 
The subtype of dementia will be determined and recorded based upon clinical 
neurologic and psychiatric evaluation to include review of all available medical 
information, medical records, documentation of prior evaluations, 
family/caretaker interviews, records, laboratory, genetics or other biomarkers, 
and results of neuroimaging (if available).  
The following scales will characterize subject’s dementia (DSM-5 Major 
Neurocognitive disorder) in terms of cognitive and functional impairment. Both 
assessments will occur at the Pre-Screening and Day 2/Follow-Up visits. 
5.4.1 MMSE 
The Folstein Mini-Mental State Examination (MMSE) is an exam that tests an 
elderly person's cognitive ability. Domains measured by the MMSE include 
orientation to time and place, registration, attention and calculation, recall, 
naming, repetition, comprehension, reading, writing, and drawing.  Total points 
on this test is 30. Any score of 24 or more (out of 30) indicates a normal 
cognition. Below this, scores can indicate severe (≤9 points), moderate (10–18 
points) or mild (19–23 points) cognitive impairment. 
5.4.2 CDR  
The CDR® (Alzheimer's Disease Research Center, Washington University, St 
Louis) is a 5-point scale used to characterize six domains of cognitive and 
functional performance applicable to Alzheimer Disease and related dementias: 
memory, orientation, judgment & problem solving, community affairs, home & 
hobbies, and personal care. A score of 0 connotes no cognitive impairment, and 
then the remaining four points are for various stages of dementia where: 
 CDR-0 = normal 
 CDR-0.5 = very mild dementia 
 CDR-1 = mild 
 CDR-2 = moderate 
 CDR-3 = severe 
5.5 PHARMACOKINETICS 
For each subject, up to 6 blood samples (24 mL of blood) will be collected during 
the study for PK analysis. Blood samples (4 ml) will be collected at 0.5, 1, 2, 4, 8, 
and 24 hours post-dose per Table 1 Schedule of Events. A sample may not be 
collected if the physician in charge of the patient indicates in the source 


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documents that the patient is in a mental state that is not conducive to PK 
sample collection and record the PEC score at the time of proposed sample 
collection.  
For re-dosed subjects only: An extra PK blood sample (4 ml) will be collected at 
2.5 hours post second dose in addition to the other times, totaling approximately 
73 ml. All PK sampling will occur only after all other assessments at that 
timepoint are conducted. 
For Part B subjects, an additional sample will be collected if possible, between 10 
and 12 hours per the Schedule of Events. 
5.6 CONCOMITANT MEDICATIONS 
Concomitant medications will be reviewed and documented each day during the 
study. 
6 
STUDY ENDPOINTS 
6.1 PRIMARY ENDPOINTS 
6.1.1 PRIMARY EFFICACY ENDPOINT 
• Change in PEC total score from baseline  
6.1.2 PRIMARY EFFICACY TIMEPOINT 
• 2 hours post-dose 
6.1.3 PRIMARY SAFETY AND TOLERABILITY ENDPOINTS 
• Comparison of cardiovascular parameters (BP, HR, pulse oximetry, ECG) 
between BXCL501 40 µg and placebo 
6.2 SECONDARY ENDPOINTS 
6.2.1 SECONDARY EFFICACY ENDPOINTS 
• Change in PEC total score from baseline at 30 min, 1 hr, 4 hr, and 8 hr 
post-dose, and at Day 2, Day 3, and Day 7  
• Percentages of subjects at each dose who achieve a 40% reduction from 
baseline in PEC total score at 2 hr post-dose (“Responders”) 
• Change in PAS total score from baseline at 30 min, 1 hr, 2 hr, 4 hr, and 8 
hr post-dose, and at Day 2, Day 3, and Day 7 
• Change in ACES score from baseline at 1 hr, 2 hr, 4 hr, and 8 hr post-
dose 
• Change in CGI-S agitation score from baseline at 2 hr post-dose and at 
Day 2 
• CGI-I agitation score at 30 min, 1 hr, 2 hr 4 hr, and 8 hr post-dose  
• Change in CMAI total score from baseline at 2 hr post-dose and Day 7 


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6.2.2 SECONDARY SAFETY AND TOLERABILITY ENDPOINTS 
• Time taken for medication to dissolve (1-30 sec, 31-59 sec, 1-2 min, 3+ 
min) – only assessed at 30 minutes 
• Negative reaction to the sublingual film in the examiner’s opinion (Yes/No) 
– assessed at 30 min, 2 hr, 4 hr, and 24 hr post-dose 
• Part B: Duration of calming, as measured by the PANSS supplementary 
items. All timepoints will be included, with the 2 hour timepoint of primary 
interest. 
6.2.3 SECONDARY PHARMACOKINETIC ENDPOINTS 
PK analyses will be specified in a separate document.  
6.3 EXPLORATORY ENDPOINTS 
• 
 
 
 
7 
STATISTICAL ANALYSES 
Statistical analyses will be performed using SAS® software version 9.4. 
7.1 STATISTICAL METHODOLOGY 
7.1.1 SAMPLE SIZE DETERMINATION 
 
 
 
 
7.1.2 POPULATIONS FOR STATISTICAL ANALYSIS 
The following are analysis populations for the study: 
• Safety Population: All subjects who receive study drug, according to the 
treatment received. The Safety Populations from both Parts A and B will be 
combined. Select tables may be generated for the Part B Safety Population 
only. 
• Intent to treat (ITT) Population: All Part B subjects in the Safety Population, 
analyzed as randomized. 
• Per Protocol (PP) Population: All subjects in the Part B ITT Population with 
no major protocol deviations likely to impact inference. PP analyses may not 
be conducted if there are not sufficient protocol deviations deemed to impact 
analysis. If subjects receive treatment other than to which they were 
randomized, they will be included in a PP analysis as treated (barring 
CCI
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protocol deviations sufficient to exclude them for other reasons). The PP 
population will be finalized prior to breaking the blind for Part B.      
7.1.3 STATISTICAL ANALYSES – GENERAL CONSIDERATIONS 
Continuous variables will be summarized by treatment using descriptive statistics 
(n, mean, median, standard deviation, minimum, and maximum). The same 
number of decimal places as in the raw data will be presented when reporting 
minimum and maximum. One more decimal place than in the raw data will be 
presented when reporting mean and standard deviation. 
For categorical variables, frequencies and percentages will be presented by 
treatment.  
Baseline is defined as the last non-missing observation prior to initiation of study 
medication.  
All statistical testing will be based on a two-sided significance level of 0.05 unless 
otherwise stated.  
Listings for Appendix 16.2 in the CSR will include all the subject data points 
being collected or derived for analyses. Data listings will be provided for all 
subjects up to the point of withdrawal. 
7.1.4 PROCEDURES FOR HANDLING MISSING DATA 
No imputation will be performed for missing data unless stated otherwise. 
For longitudinal analyses of continuous data, the Mixed Model Repeated 
Measures is considered valid under a Missing at Random (MAR) missingness 
mechanism.  Furthermore, no missing data is anticipated for the primary endpoint 
(PEC) at the primary timepoint of 2 hours.  
7.1.5 INTERIM ANALYSES 
Interim analyses are not anticipated for Part B of this study. 
7.2 SCREENING AND BASELINE CHARACTERISTICS 
Summary tables will be constructed by treatment for the Safety Population for 
Parts A and B combined for the following Pre-Screening, Screening or Pre-Dose 
data: demographic characteristics of age, sex, race, ethnicity, weight, height and 
body mass index (BMI), medical history, prior medications, laboratory 
examinations, vital signs, and ECG. 
Listings will be provided for eligibility criteria violations, demographics, and 
medical history. 
7.3 SUBJECT DISPOSITION  
Subject disposition will include the number of subjects who enroll in the study 
and the number and percentage of subjects included in each analysis population 


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by treatment. The frequency and percentage of subjects who withdraw or 
discontinue from the study, along with the reason for withdrawal or 
discontinuation, will be summarized by treatment. Subject-level listings will be 
provided. 
All reported major protocol deviations and determined exclusions from any 
analysis population(s) will be documented and included in the CSR. 
7.4 STUDY TREATMENT ADMINISTRATION 
Study drug administration data will be listed by subject. 
7.5 EFFICACY ANALYSES 
The efficacy analyses described in this section compare the 40 µg BXCL501 
group to the placebo group. Nominal significance levels will be reported with no 
adjustment for secondary endpoints. However, PEC total scores at earlier 
timepoints will be tested hierarchically to determine earliest onset of action, 
conditional upon the significance of differences between 40 µg and placebo at 2 
hours. 
The intent to treat population will be considered primary. Observations recorded 
after use of rescue medication will be censored (considered missing). 
7.5.1 PRIMARY EFFICACY ANALYSIS 
The primary efficacy endpoint is change from baseline in PEC total score. The 
primary efficacy timepoint will be at 2 hrs. post-dose.  
A mixed model for repeated measures (MMRM) will be used to assess treatment 
group differences for change from baseline. Change from baseline scores will 
include all available timepoints in a single model; the 2 hr timepoint is considered 
primary, and all other timepoints are considered secondary. Fixed effects will 
include treatment group, analysis visit, treatment-by-visit interaction, and a 
baseline-by-visit interaction. Visit will be fit as a repeated effect in the model 
using the repeated statement in SAS. The baseline score will be included as a 
continuous covariate. An unstructured covariance structure and Kenward-Roger 
degrees of freedom will be used. In the event an unstructured covariance 
structure fails to converge, a Toeplitz structure will be used.  
Least squares (LS) means will be presented for treatment at each timepoint in 
summary tables. Pair-wise comparisons of differences in LS means, two-sided 
95% confidence intervals (CIs) on differences, and p-values will be provided for 
treatment versus placebo for each visit. Line graphs will be provided reflecting 
LSM changes from baseline over time. 
Individual patient scores for the PEC for all timepoints will be provided in a listing. 


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7.5.2 SECONDARY EFFICACY ANALYSES 
Changes from baseline for PAS, ACES, CGI-S agitation score, and CMAI total 
score for all available timepoints will be analyzed using MMRM, using the 
specifications described above. CGI-I agitation score will be compared between 
treatment and placebo groups using MMRM, however as there is no baseline 
measurement, it will not be included in the model. Listings will be provided for 
individual patient scores. Line graphs will be provided reflecting changes from 
baseline over time in PAS score. 
Responder (ie, percentage change from baseline in the PEC score at 2 hours 
>40%) comparisons will be made via Fisher’s Exact test. Nominal p-values and 
the treatment difference and associated two-sided 95% confidence interval will 
be based on the Wald method with continuity correction and reported for  
BXCL501 versus placebo. A bar chart will be provided reflecting percentages of 
responders at each timepoint for the BXCL501 group and placebo.  
For the CGI-S and CGI-I, scores of 0 (not assessed) will be set to missing prior to 
analysis. 
7.5.3 EXPLORATORY EFFICACY ANALYSES 
 
 
 
 
 
 
 
7.6 SAFETY ANALYSES 
Safety analyses will be based on the Safety Population for Parts A and B 
combined. Safety and tolerability will be assessed by clinical review of all safety 
parameters including AEs, laboratory values and vital signs. The safety analyses 
will include all results collected from randomization through the end of the study. 
7.6.1 PRIMARY SAFETY ANALYSES 
Comparison of cardiovascular parameters (BP, HR) between BXCL501 40 µg 
and placebo.  
7.6.2 SECONDARY SAFETY ANALYSES 
A frequency summary will be presented for time taken for medication to dissolve 
at 30 minutes (1-30 seconds, 31-59 seconds, 1-2 minutes, 3+ minutes) and for 
negative reaction to sublingual film (Yes/No) assessed at 30 min, 2 hr, 4 hr, and 
24 hr post-dose. These parameters will be presented for each treatment group at 
CCI


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each timepoint. Listings will include subject-level findings as well as all physical 
findings noted during buccal examinations.  
7.6.3 ADVERSE EVENTS 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Affairs (MedDRA version 23.1) coding system and summarized by system organ 
class and preferred term. Clinically significant deteriorations in physical 
examination findings will be reported and summarized as adverse events.  
Abnormal, clinically significant laboratory values will be reported and summarized 
as adverse events. 
The number and percentage of patients who report TEAEs will be summarized 
by system organ class and preferred term. TEAEs will also be summarized by 
severity as well as relationship to Study Medication. For summaries by 
relationship, relationship will be categorized as related (unlikely, possibly, 
probably, and definitely related) or not related.  
Patients who report the same preferred term on multiple occasions will be 
counted once for the preferred term: under the highest severity when 
summarized by severity and under the closest relationship to Study Medication 
when summarized by relationship.  If a patient reports multiple preferred terms 
for a system organ class, the patient will be counted only once for that system 
organ class. 
Proportions for adverse events that are gender-specific (e.g., dysmenorrhea) will 
be based on the number of patients from that gender. 
The number and percentage of patients who experience TEAEs will be 
summarized by treatment group for the following: 
• By system organ class and preferred term 
• By severity, system organ class, and preferred term 
• By relationship to Study Medication (related, not related), system organ 
class, and preferred term 
• Serious adverse events by system organ class and preferred term 
• Serious adverse events by relationship to Study Medication, system organ 
class, and preferred term 
• Adverse events resulting in discontinuation of Study Medication by system 
organ class and preferred term 
By-patient listings will be provided for any deaths, serious adverse events, and 
adverse events leading to discontinuation of treatment.  


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7.6.4 COLUMBIA SUICIDE SEVERITY RATING SCALE 
The C-SSRS data will be summarized descriptively. Individual patient data will be 
provided in a listing. Only the following specific suicidal ideation and behavior 
category questions with any “Yes” responses will be summarized in a frequency 
distribution table at each post-randomization visit: 
• Any Suicidal Ideation Category: 
o Wish to be Dead 
o Non-Specific Active Suicidal Thoughts 
o Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act 
o Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
o Active Suicidal Ideation with Specific Plan and Intent 
• Any Suicidal Behavior Category: 
o Completed Suicide 
o Non-Fatal Suicide Attempt 
o Interrupted Attempt 
o Aborted Attempt 
o Preparatory Acts or Behavior 
o Any Suicidal Ideation or Behavior Category 
7.6.5 CLINICAL LABORATORY EVALUATIONS 
Each laboratory value and change from baseline (when appropriate) will be 
summarized for hematology, blood chemistry and urinalysis for each treatment 
and all available timepoints. Individual patient listings will be provided. 
7.6.6 PULSE OXIMETRY 
A listing of findings from pulse oximetry will be provided by subject. 
7.6.7 PHYSICAL EXAMINATION 
A listing of abnormal physical examination findings will be provided by subject. 
Pregnancy, alcohol screening, and drug testing results will be provided by 
patient. 
7.6.8 CLINICAL DIAGNOSIS AND DESCRIPTION OF DEMENTIA 
MMSE and CDR scores will be listed by patient. 


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7.6.9 VITAL SIGNS 
Resting, standing, and postural change (where available) vital signs will be 
summarized at each timepoint for each treatment group, using descriptive 
statistics. For any vital signs measured in triplicate, only the 2nd measurement will 
be included in the descriptive statistics. Change from baseline in vital signs 
values will also be summarized, as well as abnormal categorical postural 
changes in blood pressure (systolic blood pressure postural decrease > 20 
mmHg or diastolic blood pressure postural decrease > 10 mmHg). Individual 
patient listings will be provided. 
Postural change in vital signs (commonly referred to as “orthostatic”) is defined 
as the change from the resting to standing positions.  
Baseline will be defined as the last vital sign value obtained before the first dose 
of Study Medication on Day 1.  
7.6.10 12-LEAD ELECTROCARDIOGRAM 
The change from baseline in ECG intervals (PR, QT, QTcF, QRS, and RR) to 
each scheduled assessment will be summarized descriptively by treatment 
group.   
In addition, the number of subjects meeting the following criteria will be 
presented for each treatment at each time point: 
ECG Mean Heart Rate (beats/min): 
• Decrease in HR from baseline >25% to a HR <50 bpm 
• Increase in HR from baseline >25% to a HR >100 bpm 
 
PR Interval, Aggregate (msec): 
• Increase in PR from baseline >25% to a PR >200 msec 
 
QRS Duration, Aggregate (msec): 
• Increase in QRS from baseline >25% to a QRS >120 msec 
 
QTcF Interval, Aggregate (msec): 
• QTcF <=450 msec  
• QTcF >450 to <=480 msec  
• QTcF >480 to <=500 msec  
• QTcF >450 msec  
• QTcF >480 msec 
• QTcF >500 msec  
• ΔQTcF <=30 msec 
• ΔQTcF >30 to <=60 msec 
• ΔQTcF >60 msec 
 


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In addition, shift tables comparing QTcF interval categories from baseline to each 
post-baseline time point will be provided by treatment group for the following: 
• <=450 msec 
• >450 msec to <=480 msec 
• >480 msec to <=500 msec 
• >500 msec 
 
For the above tables, a category for baseline missing will be included, as 
needed. 
7.6.11 CONCOMITANT MEDICATIONS 
Concomitant medications will be summarized (n and %) by ATC class and 
preferred term (coded by WHO Drug coding dictionary September 2020) for each 
treatment group. Concomitant medications for individual patients will be provided 
in a listing. 
7.6.12 RESCUE MEDICATIONS 
Subjects needing rescue medications will be summarized (n and %) by time 
interval (eg, 0 to <2 hours) to first use of rescue medication for each treatment 
group. Rescue medications for individual patients will be provided in a listing. 
7.6.13 STUDY MEDICATION COMPLIANCE 
Study Medication compliance will be measured by the number of days of Study 
Medication administered and the percentage of scheduled doses that were 
taken. Descriptive statistics will be used to summarize dosing compliance within 
each treatment group, as well as provided in a listing per patient.  
7.7 PHARMACOKINETIC and PHARMACODYNAMIC ANALYSIS 
PK analyses will be specified in a separate document. Data from subjects who 
participated in the study will be included in the pharmacokinetic analysis. 
Subjects with missing sample concentrations will be included in the 
pharmacokinetic analyses provided their pharmacokinetic parameters can be 
adequately characterized based upon the remaining data. 
Deviation from procedures described in this protocol that impact the quality of 
data required to meet the objectives of the study will be documented and may 
result in exclusion of pharmacokinetic data from the analyses for a subject. This 
includes any deviations or events that would invalidate the evaluation of the 
pharmacokinetics. Examples of deviations and events which could result in 
exclusion of pharmacokinetic data from the analyses include emesis, 
immediately after dosing (within a predetermined time, to be specified in the SAP 
for PK and PK/PD analyses), sample processing or assay errors that lead to 
inaccurate bioanalytical results. Other deviations or events, which do not 
disqualify data from analyses, may require minor adjustments to calculations. If 


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these occur, data analyses will be adjusted and documented accordingly such 
that conclusions are not biased. An example of such an event includes, but is not 
limited to, minor deviations between the actual and scheduled time of sample 
collection. 
All pharmacokinetic parameters will be calculated using non-compartmental 
analysis using appropriate pharmacokinetic software. Actual sampling times will 
be used in all pharmacokinetic analyses. Per protocol times will be used to 
calculate mean plasma concentrations for graphical displays. 
Other PK analyses may be performed as appropriate. 
Pharmacodynamic data, including changes in blood pressure & heart rate, and 
changes in measures of agitation, from baseline may be evaluated as a function 
of time and as a function of measured or estimated plasma concentrations. 
Details will be described in the SAP for PK and PK/PD analyses. 
8 
REFERENCES 
Cohen-Mansfield J, Marx MS, & Rosenthal AS. (1989). A description of agitation 
in a nursing home. Journal of Gerontology: Medical Sciences, 44(3), M77-M84. 
Oquendo MA, Halberstam B, Mann JJ. Colombia Suicide Severity Rating Scale 
(C-SSRS) – Risk Factors for Suicidal Behavior: The Utility and Limitations of 
Research Instruments, in Standardized Evaluation in Clinical Practice. First MB, 
editor. American Psychiatric Publishing; Washington, DC: 2003: 103-131.  
 
 


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9 
TABLES, LISTINGS AND FIGURES 
A separate document containing the list of tables, listings, and figures (TFLs) to 
be included in the post-text Appendix 14 of the CSR will be provided. TFLs may 
be modified with Sponsor’s approval and as deemed necessary without update to 
the SAP.