A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Efficacy And Safety Study of PRN Dosing of BXCL501 Over A 12 Week Period In Subjects With Agitation Associated With Dementia
Phase: PHASE3
Conditions: Agitation, Dementia
Sponsor: BioXcel Therapeutics Inc

 
 A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, EFFICACY 
AND SAFETY STUDY OF PRN DOSING OF BXCL501 OVER A 12 WEEK PERIOD IN SUBJECTS 
WITH AGITATION ASSOCIATED WITH DEMENTIA 
 
NCT05271552 
 
November 18, 2022 

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A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
EFFICACY AND SAFETY STUDY OF PRN DOSING OF BXCL501 OVER A 12 WEEK 
PERIOD IN SUBJECTS WITH AGITATION ASSOCIATED WITH DEMENTIA 
 
 
 
PROTOCOL NUMBER:
BXCL501-303
STUDY PHASE: 
Phase 3
IND NUMBER:
156685 
PROTOCOL VERSION:
3.0
PROTOCOL DATE: 
23Feb2022 
AMENDMENT 1 
20May2022
AMENDMENT 2:
18Nov2022 
SPONSORED BY: 
BioXcel Therapeutics, Inc.
555 Long Wharf Drive 
12th Floor  
New Haven, CT 06511 
Phone: 
This study will be performed in compliance with Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the Institutional Review 
Board or Independent Ethics Committee, or as required by law. Persons to whom this 
information is disclosed should be informed that this information is confidential and may not be 
further disclosed without the express permission of BioXcel Therapeutics, Inc. 

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2.
INVESTIGATOR AGREEMENT
PROTOCOL TITLE: 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED EFFICACY AND SAFETY STUDY OF BXCL501 
FOR THE TREATMENT OF AGITATION ASSOCIATED WITH 
DEMENTIA 
 
 
PROTOCOL NUMBER:  
BXCL501-303 
 
I have read the protocol and agree that it, along with the related Clinical Trial Agreement, contains all the 
details necessary to carry out the study. I will conduct this study according to the protocol and will 
complete the study in the time agreed. Potential additions or modifications to the study will be by mutual 
written agreement between BioXcel Therapeutics, Inc. and me and will be documented and filed, if 
required, with the Institutional Review Board and the United States Food and Drug Administration. 
 
I will provide copies of the protocol and other pertinent information to all individuals responsible for 
assisting me in the study. 
 
BioXcel Therapeutics, Inc., Cognitive Research Corporation, and their designees will have access to 
source documentation from which case reports have been generated. 
 
 
Investigator 
Signature: 
_________________________________   Date:  ___________________ 
 
Investigator 
Name (print):  ___________________________________________________________ 

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7 UDS is required at Screening. UDS will be re-collected prior to dosing if more than 21 days have passed since the Screening visit. Urine drug screen will be 
analyzed by a central laboratory. 
8 In cases where repeat laboratory tests may be required to confirm eligibility prior to dosing, a local laboratory may be used to obtain repeat test results. 
912-lead ECGs at Pre-Dose need to be collected, but if unable to be acquired due to agitation it will not constitute a protocol deviation. ECGs collected following 
treatment are to be performed prior to PK sampling. Triplicate ECGs are to be obtained approximately 1-3 minutes apart.  
10 Resting vital signs (SBP, DBP and HR) will be taken upon having the subject recumbent for 5 min at Screening, at Pre-Dose, and at 1, 2, and 4 hours post-dose. 
Triplicate measurements to be performed in case of SBP <90 mmHg, DBP <60 mmHg or pulse <60 bpm. Vital signs are to be done prior to drawing PK blood 
samples. 
11Orthostatic measurements (SBP, DBP, HR) will be taken upon having the subject stand, with measurements taken upon standing after 1, 3, and 5 minutes, per 
Centers for Disease Control and Prevention guidelines for elderly at Screening, at Pre-dose, and at 1, 2, 4, 8, and 24 (Day 2) hours post-dose, and on Day 3 
post-dose. A change from supine to standing of 20 mmHg SBP or 10 mmHg DBP must be repeated. If any one of the three orthostatic BP readings (1, 3 and/or 
5 mins) show a decrease, from supine to standing, of 20 mmHg SBP or 10 mmHg DBP, the entire process will be repeated, which includes repeat resting and 
orthostatic BPs. Temperature and respiratory rate will be recorded when orthostatic measurement is indicated and are not required to be measured at resting 
vital sign timepoints. Vital signs are to be done prior to drawing PK blood samples. 
12 PK blood samples are to be collected at timepoints including pre-dose, and 1, 2, 4 and 8 hours after the first dose and fifth dose of study drug only. 
However, if the investigator documents it is not appropriate to collect a sample from the subject (e.g., inability to access a venous site to collect a blood sample 
due to psychomotor agitation, subject refusal, subject’s current physical condition) at any of the scheduled timepoints, this will not result in the ineligibility of the 
subject’s participation, should not result in early termination nor will this be considered a protocol deviation. All PK collections will have a window of ± 10 
minutes. All PK sampling will occur only after all other assessments at that timepoint are conducted. 
13Refer to Section 11.3 and Appendix 1 when Day2/24 hr and predose visits occur on the same day. 

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TABLE OF CONTENTS
1.
PROCEDURES IN CASE OF EMERGENCY ............................................................3
2.
INVESTIGATOR AGREEMENT ...............................................................................4
3.
SYNOPSIS ...................................................................................................................5
4.
TABLE OF CONTENTS ...........................................................................................17
4.1.
List of Tables ..............................................................................................................21
5.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22
6.
INTRODUCTION ......................................................................................................24
6.1.
Background and Rationale ..........................................................................................24
6.2.
Description of BXCL501 ............................................................................................24
6.3.
Non-Clinical Pharmacology .......................................................................................24
6.3.1. 
Pharmacodynamics .....................................................................................................24
6.4.
Clinical Experience and Pharmacokinetics ................................................................25
6.4.1. 
Phase 3 Study BXCL501-301 .....................................................................................25
6.4.2. 
Phase 3 Study BXCL501-302 .....................................................................................26
6.4.3. 
Intravenous Study in Alzheimer’s Disease (Study CRLIV091834) ...........................27
6.4.4. 
Phase 1b/2 Study BXCL501-103 ................................................................................28
7.
OBJECTIVES .............................................................................................................31
7.1.
Primary Objective .......................................................................................................31
7.2.
Key Secondary Objective ...........................................................................................31
8.
STUDY DESIGN .......................................................................................................32
8.1.
Overall Study Design and Plan ...................................................................................32
8.2.
Independent Data Monitoring Committee ..................................................................33
8.3.
Study Sites ..................................................................................................................33
9.
SUBJECT POPULATION .........................................................................................34
9.1.
Selection of Study Population ....................................................................................34
9.1.1. 
Inclusion Criteria ........................................................................................................34
9.1.2. 
Exclusion Criteria .......................................................................................................35
9.1.3. 
Randomization criteria prior to dosing the first dose of study drug ...........................36
9.1.4. 
Criterion for dosing study drug for subsequent episodes of agitation ........................36
9.2.
Removal of Subjects from Therapy or Assessment ....................................................36

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10.
STUDY TREATMENTS............................................................................................37
10.1.
Method of Assigning Subjects to Treatment Groups .................................................37
10.2.
Identification of Investigational Product ....................................................................37
10.3.
Treatment Administration ...........................................................................................37
10.4.
Storage ........................................................................................................................37
10.5.
Labeling ......................................................................................................................37
10.6.
Drug Accountability ...................................................................................................37
10.7.
Blinding and Unblinding Treatment Assignment .......................................................38
10.8.
Selection of Dose in the Study ....................................................................................38
10.9.
Treatment Compliance ................................................................................................39
10.10. 
Concomitant Medications ...........................................................................................39
10.10.1. 
Permitted Therapies ....................................................................................................39
10.10.2. 
Prohibited Therapies ...................................................................................................39
11.
STUDY PROCEDURES ............................................................................................41
11.1.
Screening (Within 45 days Before the First Dose of Investigational Product) ..........41
11.2.
Pre-Dose (within 90 Minutes Before the Dose of Investigational Product) ...............42
11.3.
Post-Dose Assessments (through post dose day 3).....................................................42
11.4.
Weekly Assessments (During the 12 Week [day 84/ET] Treatment Period) .............43
11.5.
Premature Discontinuation (Withdrawal) ...................................................................44
12.
STUDY ASSESSMENTS ..........................................................................................45
12.1.
Efficacy .......................................................................................................................45
12.1.1. 
PANSS-Excited Component (PEC) ............................................................................45
12.1.2.
Pittsburgh Agitation Scale (PAS) ...............................................................................45
12.1.3. 
Agitation-Calmness Evaluation Scale (ACES) ..........................................................45
12.1.4. 
CGI-S and CGI-I .........................................................................................................45
12.1.4.1. 
CGI-S ..........................................................................................................................45
12.1.4.2. 
CGI-I ...........................................................................................................................45
12.1.5. 
Drug Likability Scale ..................................................................................................46
12.1.6. 
Drug Likability Questionnaire ....................................................................................46
12.2.
Clinical Diagnosis and Description of Dementia .......................................................46
12.2.1. 
International Psychogeriatric Association Criteria for Agitation ...............................46
12.2.2. 
MMSE.........................................................................................................................47
12.2.3. 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 12 ................................48

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12.3.
Pharmacokinetics ........................................................................................................48
12.3.1.
Sample Collection & Processing ................................................................................49
12.3.2.
Sample Storage ...........................................................................................................49
12.3.3. 
Sample Shipment ........................................................................................................49
12.4.1. 
Bioanalytical Sample Analyses ..................................................................................50
12.5.
Safety ..........................................................................................................................50
12.5.1.
Adverse Events ...........................................................................................................50
12.5.1.1.
Adverse Event Definitions ..........................................................................................50
12.5.1.2. 
Eliciting and Documenting Adverse Events ...............................................................51
12.5.1.3. 
Reporting Adverse Events ..........................................................................................52
12.5.1.4. 
Follow-up of Adverse Events .....................................................................................54
12.5.2. 
Johns Hopkins Fall Risk Assessment Tool .................................................................54
12.5.3. 
C-SSRS .......................................................................................................................54
12.5.4. 
Laboratory Safety Assessments ..................................................................................54
12.5.5. 
Vital Signs ..................................................................................................................55
12.5.6. 
Electrocardiogram .......................................................................................................55
12.5.7. 
Physical Examination .................................................................................................55
12.5.8. 
Concomitant Medications ...........................................................................................56
13.
STATISTICAL METHODS .......................................................................................57
13.1.
General Considerations ...............................................................................................57
13.2.
Analysis Populations ..................................................................................................57
13.3.
Statistical Analyses .....................................................................................................57
13.3.1.
Subject Disposition and Demographic Characteristics...............................................57
13.3.2. 
Efficacy Analyses .......................................................................................................57
13.3.2.1. 
Primary Efficacy Analysis ..........................................................................................58
13.3.2.2. 
Key Secondary Efficacy Endpoints ............................................................................59
13.3.2.3. 
Continued Efficacy Endpoints ....................................................................................60
13.3.2.4. 
Other Secondary Efficacy Endpoints ..........................................................................62
13.3.3. 
Safety and Tolerability Analyses ................................................................................62
13.4.
Sample Size Determination ........................................................................................63
14.
STUDY CONDUCT ...................................................................................................64
14.1.
Sponsor and Investigator Responsibilities ..................................................................64
14.1.1. 
Sponsor Responsibilities .............................................................................................64

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14.1.2. 
Investigator Responsibilities .......................................................................................64
14.2.
Site Initiation ..............................................................................................................64
14.3.
Study Documents ........................................................................................................65
14.3.1. 
Good Clinical Practice Documents .............................................................................65
14.3.2. 
Case Report Forms .....................................................................................................65
14.3.3. 
Source Documents ......................................................................................................66
14.4.
Data Quality Control ...................................................................................................66
14.4.1.
Monitoring Procedures ...............................................................................................66
14.4.2. 
Data Management .......................................................................................................66
14.4.3. 
Quality Assurance/Audit ............................................................................................67
14.5.
Study Termination ......................................................................................................67
14.5.1. 
Regular Study Termination .........................................................................................67
14.5.2. 
Premature Study Termination .....................................................................................67
14.6.
Study Site Closure ......................................................................................................68
14.6.1. 
Record Retention ........................................................................................................68
14.6.2. 
Sample Retention ........................................................................................................68
14.7.
Changes to the Protocol ..............................................................................................69
14.8.
Use of Information ......................................................................................................69
15.
FINAL CLINICAL STUDY REPORT ......................................................................70
16.
ETHICAL AND LEGAL CONSIDERATIONS ........................................................71
16.1.
Declaration of Helsinki and Good Clinical Practice ...................................................71
16.2.
Subject Information and Informed Consent ...............................................................71
16.3.
Approval by Institutional Review Board ....................................................................71
17.
REFERENCES ...........................................................................................................72
18.
APPENDIX 1..............................................................................................................74

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List of Tables
Table 1.1: Sponsor/Contract Research Organization Contact Information ...................................3
Table 3.1: Schedule of Events – Screening, Pre-Dose, and Post-Dose Assessments ..................13
Table 3.2: Schedule of Events – Weekly Assessments ................................................................16
Table 10.1: List of Prohibited Medications Prior to and After Investigational Product 
Dosing .........................................................................................................................40
Table 12.1: Interpretation of Mini-Mental State Examination Scores ...........................................48
Table 13.1: Estimand Attributes for the Primary Efficacy Analysis .............................................58
Table 13.2: Estimand Attributes for the Key Secondary Analyses of Change from 
Baseline in total PEC score at 1 hour and at 30 minutes ............................................59

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5.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation 
Definition 
ACES
Agitation-Calmness Evaluation Scale
AD 
Alzheimer’s Disease 
ADAS-Cog 12 
Alzheimer's Disease Assessment Scale cognitive subscale
ADL 
Activities of daily living 
ADWG 
Agitation Definition Work Group 
AE
Adverse event
AESI 
Adverse event of special interest 
ANCOVA
Analysis of covariance
AUC 
Area under the plasma concentration vs time curve 
BP 
Blood pressure 
CGI-I
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Contract research organization 
C-SSRS
Columbia-Suicide Severity Rating Scale 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
EDTA
Ethylenediaminetetraacetic acid
FAS 
Full Analysis Set 
FDA
Food and Drug Administration 
GCP
Good Clinical Practices
HR 
Heart rate 
hr 
Hour
ICH 
International Council for Harmonisation 
IM 
Intramuscular 
IPA 
International Psychogeriatric Association 
IRB 
Institutional Review Board 
ITT 
Intent to Treat
IV  
Intravenous 
kg 
Kilogram 
K2EDTA 
dipotassium ethylenediaminetetraacetic acid 

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Abbreviation
Definition
LAR
Legally authorized representative
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
Min
Minutes
mL 
Milliliter 
mmHg 
Millimeters of mercury
MMSE 
Mini-Mental State Exam 
NIA-AA 
National Institute on Aging and Alzheimer's Association 
PANSS-PEC
Positive and Negative Syndrome Scale – Excited Component 
PAS 
Pittsburgh Agitation Scale 
PK 
Pharmacokinetic 
PRN 
As needed (pro re nata) 
RASS 
Richmond Agitation Sedation Scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SL 
Sublingual  
TEAE 
Treatment-emergent adverse event 
µg 
Microgram 
UDS 
Urine drug screen 
US 
United States 
UTI
Urinary tract infection

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6.
INTRODUCTION
6.1.
Background and Rationale
Acute agitation is a severe, disruptive, and distressful complication of many chronic mental 
illnesses, including schizophrenia (Osser and Sigadel, 2001), bipolar disorder (Alderfer and 
Allen, 2003) and dementia (Conn and Lieff, 2001). Current standard of care treatment of an 
acute episode of agitation is pharmacological tranquilization with antipsychotics (either typical 
or atypical) and/or benzodiazepines (Currier and Trenton, 2002; Currier et al., 2004; 
Battaglia, 2005). These drugs are available in a variety of forms, including oral tablets, 
orally-disintegrating tablets, oral liquids, and intramuscular injections (IM). Efficacy has been 
demonstrated for each of these agents, but some are characterized by slow onset of action, 
potentially prolonging the suffering of agitated patients and increasing the need for physical 
restraint or seclusion (Allen et al., 2003). 
BXCL501, an orally dissolving film of dexmedetomidine, is designed as a self-administered, 
low-dose, sublingual film with mucoadhesive properties. It is expected that its administration in 
agitated patients will lead to a clinically-meaningful reduction in agitation without excessive 
sedation or use of antipsychotics or intramuscular preparations. This study is designed to assess 
safety and efficacy of up to 28 doses of BXCL501 administered for the acute treatment of 
clinically significant agitation episodes over a study period of 12 weeks. When an episode of 
agitation occurs that meets dosing criteria, subjects may be dosed with BXCL501 40 µg or 60 µg 
doses, or placebo. BXCL501 will be evaluated in male and female subjects, 65 years and older, 
who require minimal supervision or minimal assistance with their ADLs and reside in a facility 
where such assistance is available. Subjects who meet the criteria for a diagnosis of probable 
Alzheimer’s Disease (AD) are eligible for the study. The criteria for probable AD are provided in 
McKhann et al, 2011). 
6.2. 
Description of BXCL501 
BXCL501 is a sublingual film comprised of dexmedetomidine, the active pharmaceutical 
ingredient and the following inactive ingredients: polyethylene oxide, hydroxypropyl cellulose, 
sucralose, peppermint oil, Emerald Green colorant, and Food, Drug, and Cosmetic Act Blue #1 
colorant. 
No special transport or storage conditions are required for BXCL501. Packaged films can be 
stored at room temperature (25°Celsius) and ambient humidity. 
6.3. 
Non-Clinical Pharmacology 
6.3.1. 
Pharmacodynamics 
Medetomidine is a racemic mixture of 2 stereoisomers: dexmedetomidine and 
levomedetomidine. The active isomer is dexmedetomidine, whereas the other isomer, 
levomedetomidine, is non-active. 
2 adrenoceptor agonist 
on presynaptic neurons. The stimulation of these receptors leads to a decrease in norepinephrine 
release from presynaptic neurons with inhibition of postsynaptic activation, which attenuates 
CNS arousal, especially in the locus coeruleus of the brain (MHRA, 2014). 

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Since the pharmacologic effects of IV dexmedetomidine have been characterized, BioXcel 
sought to evaluate various dexmedetomidine metrics following administration by the sublingual 
(SL) route. BioXcel Therapeutics, Inc. conducted 3 nonclinical studies to evaluate the 
pharmacodynamics of different BXCL501 formulations as compared to dexmedetomidine 
administered by different routes, including sublingual liquid administration. 
Overall, the studies demonstrated that sublingual administration in animal models produce 
sufficient exposure to elicit a calming effect in a rat model of aggressive behavior (intruder 
model). 
 
Clinical Experience and Pharmacokinetics 
Phase 3 Study BXCL501-301 
Study BXCL501-301 was a Phase 3 multicenter, randomized, double-blind, placebo-controlled 
study to determine efficacy and safety of BXCL501 in agitation associated with schizophrenia 
with 3 dosing groups (BXCL501 120 µg, BXCL501 180 µg, and placebo). The study was 
conducted at 15 investigative sites in the United States. 
Male and female patients, between the ages of 18 to 75 years, who had met Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia, 
schizoaffective, or schizophreniform disorder were eligible for the study. 
The primary objective of this study was to determine if a single dose of BXCL501 effectively 
reduces symptoms of acute agitation associated with schizophrenia, schizoaffective disorder or 
schizophreniform disorder. The primary efficacy endpoint was mean change from baseline in 
PEC total score at 2 hours following the administration of BXCL501 180 µg and BXCL501 
120 µg, compared to placebo. 
A total of 380 subjects were enrolled in the study. Of these subjects, all received 1 or more doses 
of investigational product: 125 (BXCL501 180 µg), 129 (BXCL501 120 µg), and 126 (placebo). 
schizoaffective, or schizophreniform disorder. The treatment produced a rapid calming effect. 
In this study, the primary efficacy endpoint was met in both BXCL501 treatment groups. At 
2 hours post-dose, significant improvements (ie, decreases) from baseline in PEC total scores 
placebo. Mean changes from baseline were -10.4 points and -8.4, respectively, versus -4.7 for 
placebo. LSM differences from placebo were -5.5 (P <0.0001) and -3.7 (P <0.0001) for the 
180 
, respectively. 
The secondary efficacy endpoint (ie, the earliest time where an effect on agitation was apparent) 
was also met. As early onset of action is an important attribute for therapy in reducing agitation, 
20 minutes post dosing (LS mean difference of -1.2 [P = 0.0032]), and at 30 minutes post-dose 
the LS mean difference was clinically meaningful (-2.4, P <0.0001). Continuous improvements 
were demonstrated from 30 minutes with a peak effect at 2 hours post-dosing. Statistically 
-
dose (LS mean difference of -1.3 [P = 0.0075]) and at 45 minutes post-dose the LS mean 

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difference was clinically meaningful (-2.1, P <0.0001). Continuous improvements from that 
point forward were observed with a peak effect also at 2 hours post-dosing. 
All exploratory endpoints (ie, PEC responders, CGI-I, CGI-I responders, Agitation-Calmness 
Evaluation Scale [ACES], and PANSS total score) supported the efficacy of BXCL501 in 
reducing agitation. 
generally well tolerated and had a favorable safety profile in the treatment of subjects with 
agitation. The TEAEs reported in this study were consistent with known common side effects of 
dexmedetomidine, namely dry mouth, bradycardia, hypotension, and somnolence. A higher 
somnolence compared with placebo-treated subjects. Most events of somnolence were 
considered to be mild in severity; none were considered to be severe. It is important to note that 
there were no cases of syncope or falls reported in this study. 
 
Phase 3 Study BXCL501-302 
Study BXCL501-302 was a Phase 3 multicenter, randomized, double-blind, placebo-controlled 
study to determine efficacy and safety of BXCL501 in agitation associated with bipolar disorder 
with 3 dosing groups (BXCL501 120 µg, BXCL501 180 µg, and placebo). The study was 
conducted at 15 investigative sites in the United States. 
Male and female patients, between the ages of 18 to 75 years, who had met DSM-5 criteria for 
bipolar I or bipolar II disorder were eligible for the study. 
A total of 380 subjects were enrolled in the study. Of these subjects, 378 received 1 or more 
doses of study drug and comprised the Safety Population (126 subjects each in the BXCL501 
compared to placebo. The treatment produced a rapid calming effect. 
In this study, the primary efficacy endpoint was met in both BXCL501 treatment groups. At 
2 hours post-dose, significant improvements (ie, decreases) from baseline in PEC total scores 
wer
placebo. Mean changes from baseline at 2 hours post-dose were -10.4 and -9.0 points, 
respectively, versus -4.9 for placebo; LSM mean differences from placebo were -5.4 (P< 0.0001) 
and -
 
Significant and clinically meaningful improvements from baseline in PEC total scores were 
maintained at 4, 6, and 8 hours post-
hanges of 
-9.9, and -9.1, respectively, with P < 0.0001 for all timepoints. The same pattern was 
observed in the BXCL501 
-9.5, -9.2, and -8.5, 
respectively, with P < 0.0001 for all timepoints. 
As rapid onset of action is an important attribute for therapy in reducing agitation, the BXCL501 
-dose 
(LSM difference of -1.1 [P = 0.0070]). At 30 minutes post-dose a statistically significant 
improvement was also observed (LS mean difference of -1.7 [P = 0.0006]) with a peak efficacy 

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effect at 2 hours post dose (LSM difference of -5.4 [P < 0.0001]). Statistically significant 
red at 20 minutes post dose (LSM 
difference of -1.0 [P = 0.0092]) and continuous improvements were evident from that point 
forward with a peak effect also at 2 hours post-dose (LSM difference of -4.1 [P < 0.0001]). 
All exploratory endpoints (ie, PEC responders, CGI-I, CGI-I responders, ACES, and Young 
Mania Rating Scale) supported the efficacy of BXCL501 in reducing agitation. 
Changes in secondary efficacy measures (ie, CGI-I and ACES scores) at 2 hours post-dose were 
consistent with the results for PEC total scores and were indicative of improvement in symptoms 
of agitation after treatment with BXCL501. 
The safety data collected in this study showed that BXCL501 was generally well tolerated and 
had a favorable safety profile in the treatment of subjects with agitation. The TEAEs reported in 
this study were consistent with known common side effects of dexmedetomidine, namely dry 
mouth, bradycardia, hypotension, and somnolence. A higher proportion of subjects in the 
d TEAEs of somnolence compared with 
placebo-treated subjects. Most events of somnolence were considered to be mild in severity, and 
none were considered to be severe. It is important to note that there were no cases of syncope or 
falls reported in this study. 
 
 
BioXcel conducted a study to determine the safety and tolerability of intravenous (IV) 
dexmedetomidine in a geriatric population (Study CRLIV091834). This was a randomized, 
blinded, prospective, placebo controlled, parallel design, single center, investigator-initiated 
study conducted to evaluate the efficacy and safety of dexmedetomidine in the agitated subjects 
with mild probable Alzheimer’s Disease (treatment allocation 5:2).
Subjects were male and female ranging from 55 to 75 years (both inclusive) of age with known 
cases of Mild Probable Alzheimer’s Disease in accordance with the National Institute of 
Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related 
Disorders Association criteria for diagnosis of Alzheimer’s Disease with a MMSE score between 
20 – 24. A total of 14 subjects meeting the eligibility criteria as per protocol were randomized in 
the study, 10 subjects received dexmedetomidine IV infusion and 4 subjects received placebo 
treatment. 
The primary endpoint was to determine the optimal IV dose and safety of dexmedetomidine in 
the target population by achieving calmness (Richmond Agitation Sedation Scale score [RASS] 
of -1 (Drowsiness, not fully alert easily awakened to voice, able to converse). Other objectives 
included how long the calming effect persists after discontinuation of study drug administration 
and to determine whether neurological effects like cognitive functioning, alertness/awareness, 
balance, and reaction time persist after drowsiness has resolved. The study also determined 
whether there were any adverse effects on blood pressure, heart rate, or respiration. 
The initial dose of dexmedetomidine was 0.1 µg/kg/hour, with no loading dose with the desired 
endpoint being the attainment of easily arousable drowsiness (RASS -1) which can be reversed 
temporarily by verbal stimulation. Once the participant was drowsy but able to respond to verbal 
stimulation, the infusion was stopped, and time was recorded. The infusion was continued for up 
to 2.5 hours up to the maximum dose. 

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Results demonstrated that 7 out of 10 subjects achieved a RASS score of -1 with 
dexmedetomidine IV infusion, while only 1 out of 4 subjects achieved a RASS score of -1 with 
placebo IV infusion. The study demonstrated that dexmedetomidine IV infusion is effective in 
reducing agitation in the subjects with mild probable Alzheimer’s Disease. It was safe and well 
tolerated without any clinically adverse effects on blood pressure and/or heart rate. 
 
Phase 1b/2 Study BXCL501-103  
Study BXCL501-103 was an adaptive Phase 1b/2 study design. It was 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 who were in an assisted living facility. The study was 
conducted at 4 investigative sites in the United States. 
The study was designed to characterize a safe and tolerable dose range that would result in a 
calming effect as measured using the Pittsburgh Agitation Scale (PAS) by evaluating at least 
10 subjects (4:1 randomization to BXCL501:placebo) at each of the 3 BXCL501 dose levels 
(30 µg, 60 µg, and 90 µg). 
The primary objective of the study was to describe the safety and tolerability of single doses of 
BXCL501 for study of efficacy in treatment of acute agitation associated with dementia. The 
primary efficacy endpoint was mean change from baseline in PEC total score at 2 hours 
following the administration of BXCL501 30 µg, 60 µg, and 90 µg, compared to placebo. 
A total of 54 subjects were enrolled and randomized: 16 (BXCL501 30 µg), 20 (BXCL501 
60 µg), 4 (BXCL501 90 µg), and 14 (placebo); 54 subjects were in the Safety Population and 
50 subjects were in the ITT population. All subjects completed the study. 
When a blinded safety review of data from the 3 cohorts (BXCL501 30 µg, 60 µg, and 90 µg) 
suggested a potential dose-related increase in transient, reversible, known, expected and 
well-described adverse events the sponsor decided not to pursue the BXCL501 90 µg dose. 
Given that the subjects in this study are elderly, generally frail and suffer from dementia and out 
of an abundance of caution the sponsor decided not to pursue the BXCL501 90 µg dose. Thus, 
the safety assessment was focused on the BXCL501 30 µg and 60 µg treatment groups. 
Please note that the 4 subjects who received BXCL501 90 µg were not included in the ITT 
population for the efficacy analysis; they were included in the Safety Population. 
Efficacy 
In the ITT Group (N=50), mean (SD) baseline PEC total score was 16.6 (3.5) in the BXCL501 
60 µg, 18.3 (1.5) in the BXCL501 30 µg group, and 16.6 (2.7) in the placebo group. These 
scores indicate that most subjects had moderate agitation at baseline.
The primary efficacy endpoint was met in both BXCL501 treatment groups. At 2 hours 
post-dose, significant improvements (ie, decreases) from baseline in PEC total scores were 
observed in the BXCL501 60 µg and BXCL501 30 µg treatment groups compared to placebo. 
Mean changes from baseline were -7.1 points and -5.7, respectively, versus -2.5 for placebo. 
LSM differences from placebo were -4.6 (P = 0.0002) and -3.2 (P = 0.0149) for the BXCL501 
60 µg and 30 µg treatment groups, respectively. 

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Significant and clinically meaningful improvements from baseline in PEC total scores were also 
observed at 1, 4, and 8 hours post-dose in the BXCL501 60 µg group with LS mean changes 
of -5.5, -8.3 and -9.3, respectively, with P values of 0.0006, 0.0004, and <0.0001, respectively. 
For the BXCL501 30 µg dose group, a significant and clinically meaningful improvements from 
baseline in PEC total score were also observed at 30 minutes post-dose and at 4 hours post-dose 
with LS mean changes of -2.1 (P = 0.0295) and -6.8 (P = 0.0216), respectively. 
considered to be treatment responders. At 2 hours post-dose, response rates in the BXCL501 
60 µg and 30 µg dose groups were significantly higher (70.0% [P < 0.0001]) and 31.0% 
[P = 0.0447], respectively, compared with placebo [0%]). 
Mean PAS total scores at baseline across the treatment groups ranged from 8.7 to 9.1 (PAS total 
scores can range from 0 to 16). At 2 hours post-dose, mean PAS total score was 3.3 in the 
BXCL501 60 µg group and 4.8 in the BXCL501 30 µg group. LS mean changes from baseline 
were -5.9 (P<0.0001) in the BXCL501 60 µg and -4.1 (P=0.0195) in the BXCL501 30 µg group. 
These changes indicated clinically meaningful improvements in agitation. Significant and 
clinically meaningful improvements in agitation were also observed at 1, 4, and 8 hours 
post-dose in the BXCL501 60 µg group with LS mean changes of -4.0, -6.3 and -6.1, 
respectively, with P values of 0.0017, 0.0004, and 0.0004, respectively. 
Agitation was significantly reduced in the BXCL501 treatment groups compared with placebo 
based on the Modified Cohen-Mansfield Agitation Inventory. LS mean reduction in the Modified 
Cohen-Mansfield Agitation Inventory total score from baseline to 2 hours post-dose was -14.0 
points (P<0.0001) in the BXCL501 60 µg group, -8.2 points in the BXCL501 30 µg group (P = 
0.0364), compared with -2.9 points in the placebo group. 
Mean ACES scores at baseline across the treatment groups ranged from 1.8 to 2.1 which 
indicated “moderate agitation” (score of 2). Significant increases in calming effect were 
observed in the BXCL501 60 µg group with LS mean changes from baseline of +1.1 
(P = 0.0075) at 1 hour post-dose and +2.6 (P = 0.0004]) at 2 hours post-dose. These significant 
increases in calming effect were also observed at 4 hours and 8 hours post-dose (+2.7 
[P <0.0001] and +2.2 [P <0.0001], respectively). In the BXCL501 30 µg group numerical 
increases in ACES score were observed at 1, 2, 4, and 8 hours post-dose, however, none of the 
increases were statistically significant compared with placebo.
Safety
When a blinded safety review of data from the 3 cohorts (BXCL501 30 µg, 60 µg, and 90 µg) 
suggested a potential dose-related increase in transient, reversible, known, expected and 
well-described adverse events, the sponsor decided not to pursue the BXCL501 90 µg dose. 
Given that the subjects in this study are elderly, generally frail and suffer from dementia and out 
of an abundance of caution the sponsor decided not to pursue the BXCL501 90 µg dose. 
The proportion of subjects who experienced TEAEs was similar in the BXCL501 30 µg and 
60 µg groups (68.8% and 70.0%, respectively) and higher (100%) in the BXCL501 90 µg group; 
no subject in the placebo group reported a TEAE. None of the subjects experienced a TEAE that 
was considered to be severe in intensity. There were no SAEs or deaths reported and no subject 
in any of the treatment groups discontinued (ie, withdrew) from the study due to an AE. 

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The TEAEs reported in this study were consistent with known common side effects of 
dexmedetomidine, namely dry mouth, bradycardia, hypotension, and somnolence. 
The most frequently reported TEAE in the BXCL501 30 µg, 60 µg, and 90 µg treatment groups 
was somnolence (56.3% [n=9], 60.0% [n=12], and 75.0% [n=3], respectively); placebo was 0%. 
All cases of somnolence were considered by the investigator to be mild in severity, with the 
exception of 1 subject (103-01-037) in the BXCL501 60 µg cohort whose case was considered to 
be moderate in severity and not serious. 
Hypotension was reported in only 3 subjects, of which 2 subjects were in the BXCL501 60 µg 
group (severity was mild in 1 subject and moderate in the other subject) and 1 subject was in the 
BXCL501 90 µg group (severity was mild). 
A total of 5 subjects experienced TEAEs of orthostatic hypotension: 3 (75.0%) subjects in the 
BXCL501 90 µg group (all mild in severity), 1 (6.3%) subject in BXCL501 30 µg group 
(moderate in severity), and 1 (5.0%) subject in the BXCL501 60 µg group (mild in severity). 
No cases of syncope or falls were reported in this study. 
The Sponsor is exploring a BXCL501 40 µg dose in an extension of this study. 

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7.
OBJECTIVES 
7.1.
Primary Objective 
To determine the safety and efficacy of BXCL501 dosing for episodes of agitation associated 
with dementia when they occur (given as needed [PRN]), for a maximum of 28 doses within a 12 
week treatment period. 
7.2. 
Key Secondary Objective 
To determine the earliest time at which an effect on agitation is apparent, as measured by change 
from baseline in Positive and Negative Syndrome Scale – Excited Component (PEC) total score. 

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8.
STUDY DESIGN
8.1.
Overall Study Design and Plan
This is a randomized, double-blind, placebo-controlled, parallel group, 3-arm study assessing 
efficacy, safety, and tolerability of two doses of BXCL501 in male and female subjects (65 years 
and older) with acute psychomotor agitation. BioXcel Therapeutics intends to conduct this study 
in subjects who have a diagnosis of probable AD dementia based on NIA-AA criteria (2018) and 
explore the efficacy and safety of an “as needed” BXCL501 dosing regimen on agitation in these 
subjects. Prior to screening, subjects will be monitored by the research staff for frequency and 
characterization of agitation episodes for a period of 2 weeks to establish a baseline of frequency. 
Subjects will be dosed PRN with a maximum of 28 doses over a 12-week period. Subjects may 
only be dosed once per day; Day 84 is the last day a subject may receive a dose of study drug. 
Once a subject has received 28 doses of BXCL501, they will continue to be followed for the 
remainder of the 12-week study period. Day 84 is the last day that a subject can receive a dose of 
study drug. It is expected that not all episodes of agitation will be able to be assessed due to 
timing of the episodes and other factors. Every attempt will be made to capture and treat the 
majority of episodes. Subjects will receive a single film consisting of BXCL501 40 µg dose or 
BXCL501 60 µg dose or placebo in a 1:1:1 randomization scheme. Randomization will be 
stratified based on antipsychotic use in the past month. Subjects must reside in a care facility 
where all study-related procedures and study drug dosing will be performed by trained research 
staff under the supervision of the Principal Investigator. The staff at the care facility will work in 
collaboration with the Principal Investigator/research staff to identify potentially qualifying 
agitation episodes. The research staff will be responsible for assessing the agitation episode to 
determine eligibility and appropriateness to administer a dose of study drug. 
At the time of dosing, subjects will be instructed on how to take the investigational product 
sublingually and be made aware that they should retain the investigational product in the 
sublingual until dissolved. The subject will self-administer under the supervision of a trained 
research staff member. Placement of the strip will be confirmed and documented. The oral cavity 
will be checked for irritation periodically after dosing and over the course of the study. 
Participants will be allowed fluids as desired at least 15 minutes after completion of dosing. If 
the subject is unable to self-administer and has not received drug, the event will be recorded, and 
the subject's participation will continue in order to ascertain the number of agitation episodes for 
which the subject was able to self-administer and the number of agitation episodes for which the 
subject was not able to self-administer.
Up to 1 hour prior to dosing, blood pressure (BP) and orthostatic BP will be collected only if 
possible. Every effort should be made to ensure the subject is well-hydrated prior to dosing. 
Research staff should remain with the subject for the first 2 hours after dosing as other 
assessments will need to be performed. 
Safety, efficacy, and tolerability will be measured periodically throughout the treatment period 
according to the timepoints provided in the Schedule of Events tables (Table 3.1 and Table 3.2). 
All efforts should be made to complete all assessments as per protocol. Should the subject’s 
status warrant it, standard of care rescue treatment for agitation may be initiated at any time, 
preferably after the 4-hour assessments are completed. 

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Any abnormal vital sign measurement, clinical laboratory test, physical examination finding, or 
ECG parameter taken during Screening and deemed clinically significant by the investigator will 
be repeated. If the value returns to baseline (or within normal limits) or the investigator deems 
the abnormality to be stable and no longer of clinical concern the subject can be randomized into 
the study. 
8.2. 
Independent Data Monitoring Committee 
This study will be monitored under the supervision of a Data Monitoring Committee (DMC) 
which is independent from the Sponsor. The DMC is comprised of externally based individuals 
with expertise in clinical research and biostatistics. The primary responsibilities of the DMC are 
to review and evaluate the safety data during the course of the study and make appropriate 
recommendations regarding the conduct of the clinical study to the Sponsor. 
The DMC structure, roles and responsibilities, procedures, and safety data to be reviewed by the 
DMC are described in the DMC charter. In the above capacities, the DMC is advisory to the 
Sponsor. The Sponsor is responsible for promptly reviewing and for taking into account in a 
timely manner, the recommendations of the DMC in terms of study continuation with or without 
alterations or of potential study termination. 
The DMC meetings will occur as outlined in the DMC Charter, but can be convened at any time 
at the discretion of the DMC chair or the study medical officer. The DMC chair will be notified 
by the study medical officer of all SAEs and will receive summaries of other safety data as 
available. 
The responsibilities of the DMC include: 
 Evaluating the progress of the study, subjects’ risk versus benefit, and other factors that 
could affect the study outcome 
 Considering relevant information that may have an impact on the safety of the 
participants or the ethics of the study 
The DMC Charter will be provided upon request. 
8.3.
Study Sites
The study will be conducted at up to 30 sites in the US. 

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9.
SUBJECT POPULATION
9.1.
Selection of Study Population
Individuals with probable AD dementia are eligible for enrollment in this study. Subjects must 
require at least minimal assistance with activities of daily living (e.g., bathing, dressing and 
toileting) and reside in a facility where such assistance is available. Most subjects enrolled in the 
study are expected to be ambulatory. A maximum of 15 non-ambulatory subjects representing 
~10% of the total number of subjects will be enrolled. Subjects, or their LAR if necessary, will 
sign an ICF before any study-related procedures are performed.
9.1.1.
Inclusion Criteria
A subject will be eligible for inclusion in the study if he or she meets the following criteria:
Male and female subjects 65 years and older.
All subjects must have a diagnosis of probable Alzheimer’s disease based on NIA-AA 
criteria (2018). If patient biomarker data are unavailable, per the 2018 
NIA-AA diagnostic criteria, the clinical diagnosis of probable AD will be based on the 
2011 NIA-AA criteria. 
Episodes of psychomotor agitation (e.g., kick, bite, flailing) to the point that it impairs 
social activities, requires staffing, or medical intervention, or impairs ability for 
functional activities of daily living should be observed if possible 2 weeks prior to 
Screening.
Subjects exhibit behaviors that are congruent with the International Psychogeriatric 
Association criterion for agitation representing a change from the subject’s usual 
behavior. 
Subjects who have a score of 15 to 23 on the Mini-Mental State Exam (MMSE) at 
Screening and at Pre-dose and require at least minimal assistance with activities of daily 
living (e.g., bathing, dressing, and toileting). 
Subjects who read, understand, and provide written informed consent, or who have a 
LAR to provide consent on their behalf.  
Subjects who are deemed to be medically appropriate for study participation by the 
principal investigator supported by a detailed medical history, physical examination, 
12-lead ECG, blood chemistry profile, hematology, and urinalysis.
Female participants, if of child-bearing potential and sexually active, and male 
participants, if sexually active with a partner of child-bearing potential, who agree to use 
a medically acceptable and effective birth control method throughout the study and for 
one week following the end of the study. Medically acceptable methods of contraception 
that may be used by the participant and/or his/her partner include abstinence, birth control 
pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with 
foam or spermicide, vaginal spermicidal suppository, surgical sterilization, and progestin 
implant or injection. Prohibited methods include the rhythm method, withdrawal, 
condoms alone, or diaphragm.
Subjects who are at their current location for at least 14 days before Screening and plan to 
remain at the same location for the duration of the study. 
Subjects must be able to self-administer study drug. 

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Subjects who are on a stable concomitant medications regimen for the treatment 
(including off-label agents for the prevention of agitation) of any concurrent conditions 
for at least 2 weeks prior to the Screening Visit.
9.1.2.
Exclusion Criteria
A subject will be excluded from the study for any of the following reasons: 
Subjects with dementia or other memory impairment not due to probable AD, such as 
mixed or vascular dementia, dementia with Lewy bodies, Parkinson’s disease dementia, 
frontotemporal dementia, substance-induced dementia, HIV-dementia, traumatic brain 
injury, normal pressure hydrocephalus, or any other specific non-Alzheimer’s-type 
dementia.
Clinical diagnosis of probable AD should not be applied when there is evidence of a 
cerebrovascular incident temporally related to the worsening of cognitive function. 
Subjects with agitation caused by acute intoxication must be excluded. Positive 
identification of non-prescription drugs during urine screening excludes the subject. 
Subjects with significant risk of suicide or homicide per the investigator’s assessment, or 
any patient with an answer of “yes” to item 4 or 5 on the Columbia-Suicide Severity 
Rating Scale (C-SSRS) must be excluded. 
Subjects who have hydrocephalus, seizure disorder, or history of significant head trauma, 
subarachnoid bleeding, brain tumor, encephalopathy, meningitis, or focal neurological 
findings, with a recent (1 year) large (non-microvascular) stroke who may be considered 
medically unstable or in recovery must be excluded. 
 
Note: Subjects with a remote (>5 years) history of stroke may be included, regardless 
of size/location.
Subjects with laboratory or ECG abnormalities (e.g., advanced heart block [second-
degree or above atrioventricular block without pacemaker], diagnosis of sick sinus 
syndrome) considered clinically significant by the investigator or qualified designee and 
that would have clinical implications for the subject’s participation in the study must be 
excluded. 
Subjects with serious, unstable, or uncontrolled medical illnesses must be excluded. 
These include current moderate to severe hepatic impairment, or renal, gastro-
enterologic, respiratory, cardiovascular (including ischemic heart disease, congestive 
heart failure), endocrinologic, or hematologic disease. 
Subjects who have received an investigational drug within 30 days prior to Screening 
must be excluded. 
Subjects who are considered by the investigator, for any reason, to be an unsuitable 
candidate for receiving dexmedetomidine or who are unable to use the sublingual film 
must be excluded, e.g., subjects with a history of allergic reactions to dexmedetomidine. 
Subjects whose agitation is attributed to pain or infection, concomitant medication, 
environmental conditions, or psychiatric condition other than dementia as determined by 
the investigator. 
Subjects with any other condition, which in the judgment of the investigator would 
prevent them from entering or completing the study, such as recent clinical weight loss, 
chronic dehydration, or a recent clinically significant infection are excluded. 

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Subjects who are currently suffering from substance abuse. 
Subjects who have had surgery within 30 days prior to Screening or scheduled surgery 
during the study period. 
Subjects who are pregnant or breast feeding. 
Patients with a potential cause for delirium (relatively recent onset agitation and 
dementia).
9.1.3.
Randomization criteria prior to dosing the first dose of study drug
Subjects must have a total 
Subjects who are judged to be clinically agitated at pre-
the 4 items (aberrant vocalization, motor agitation, aggressiveness, and resisting care) 
comprising the Pittsburgh Agitation Scale (PAS). 
Criterion for dosing study drug for subsequent episodes of agitation
. 
9.2.
Removal of Subjects from Therapy or Assessment
All subjects are free to withdraw from participation in this study at any time for any reason and 
without prejudice. 
The investigator may terminate dosing for a subject at any time for lack of therapeutic effect, 
intolerability to the subject or reportable AEs, intercurrent illness, noncompliance with study 
procedures, administrative reasons, or unsuitability for the study in the investigator’s opinion to 
protect the subject’s best interest.
If a subject is withdrawn from dosing before completing the study, the reason for withdrawal will 
be entered on the appropriate case report form (CRF). Whenever possible and reasonable, 
evaluations that were scheduled for study completion should be performed at the time of 
premature discontinuation of dosing. Subjects who discontinue from the study will not be 
replaced.

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10.
STUDY TREATMENTS
10.1.
Method of Assigning Subjects to Treatment Groups
Upon confirmation of eligibility following Screening and Pre-dose assessments, subjects will be 
randomized 1:1:1 to receive BXCL501 40 µg, BXCL501 60 µg, or matching placebo film. 
Randomization will be stratified based on antipsychotic use in the past month. 
Study randomization will be computer generated. 
10.2. 
Identification of Investigational Product 
BXCL501 will be provided as a thin, solid-dose film formulation of dexmedetomidine, 
approximately 286 mm2 in area, designed to dissolve in the sublingual. Dosing delivers 40 µg or 
60 µg sublingually. 
Matching placebo films will be provided. 
10.3. 
Treatment Administration 
At the time of dosing, subjects will be instructed on how to take the investigational product 
sublingually and be made aware that they should retain the investigational product in the 
sublingual until dissolved. The subject will self-administer under the supervision of trained 
research staff. Placement of the strip will be confirmed and documented. The oral cavity will be 
checked for irritation periodically after dosing and over the course of the study. Participants will 
be allowed fluids as desired at least 15 minutes after completion of dosing. If the subject is 
unable to self-administer and has not received drug, the event will be recorded, and the subject's 
participation will continue in order to ascertain the number of agitation episodes for which the 
subject was able to self-administer and the number of agitation episodes for which the subject 
was not able to self-administer. 
 
Storage 
BXCL501 packaged films must be stored at room temperature (20-25°C/68-77°F with allowed 
excursion of 15-30°C/59-86°F). Store in the original package. 
10.5.
Labeling
Each container of study drug will be labeled with study-specific information that meets all 
applicable regulatory requirements. 
10.6. 
Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of study drug, including the date, quantity, batch or code number, and identification 
of subjects (subject number and initials) who received study drug. The investigator will not 
supply study drug to any person except those named as sub-investigators on the FDA 1572, 
designated staff, and subjects in this study. The investigator will not dispense study drug from 
any sites other than those listed on the FDA 1572. Study drug may not be relabeled or reassigned 
for use by other subjects. 

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Upon completion of the study, unused supplies of study drug will be reconciled by the 
investigator and returned to the sponsor or destroyed as directed. 
10.7. 
Blinding and Unblinding Treatment Assignment 
The subject, investigator and study staff will be blinded to study treatment. BXCL501 or placebo 
film will be provided and administered per Section 10.3 of this protocol. 
Treatment assignment for an individual subject should be unblinded only in an emergency, when 
knowledge of the treatment assignment is urgently needed for the clinical management or 
welfare of the subject. The investigator should contact the medical monitor before unblinding, 
when possible, but priority should be given to treatment of the subject. If unblinding occurs 
without prior approval, the investigator should promptly communicate the circumstances leading 
to the unblinding by telephone and in writing to the medical monitor. 
Breaking of the blind, other than as described above, will be considered a protocol violation. For 
any subject whose study drug treatment is unblinded, the date, time, and reason for the 
unblinding must be documented. 
10.8. 
Selection of Dose in the Study 
Previous clinical studies with the sublingual film, described above in Section 6.4, provide direct 
evidence that the exposures from the film are substantially lower than those achieved with the 
approved intravenous formulation. In translational proof of confidence studies using IV 
dexmedetomidine in healthy elderly volunteers, agitated patients with schizophrenia as well as 
agitated elderly patients with dementia, IV infusion achieved calming effects with exposures in 
the range of proposed doses for this trial (10 µg to 180 µg BXCL501). In agitated patients, mild 
calming effects became evident with plasma exposures that equate with a 20 µg to 40 µg 
BXCL501 dose. Across translational studies using IV administration and studies delivering 
dexmedetomidine via BXCL501, relative to approved IV dexmedetomidine use, low exposure 
was safe and well-tolerated demonstrating calming effects without excessive sedation in agitated 
populations. There were also no serious or severe adverse events, or clinically meaningful 
changes in heart rate or blood pressure. 
Study BXCL501-103 assessed efficacy, PK, safety, and tolerability of BXCL501 doses of 30 µg, 
60 µg, and 90 µg in adult (65 years and older) males and females with acute agitation associated 
with dementia. The primary efficacy endpoint was met in both the BXCL501 30 µg and 60 µg 
treatment groups. At 2 hours post-dose, significant improvements (ie, decreases) from baseline in 
PEC total scores were observed in the BXCL501 60 µg and BXCL501 30 µg treatment groups 
compared to placebo. Mean changes from baseline were -7.1 points and -5.7, respectively, versus 
-2.5 for placebo. LSM differences from placebo were -4.6 (P = 0.0002) and -3.2 (P = 0.0149) for 
the BXCL501 60 µg and 30 µg treatment groups, respectively (see Section 6.4.4). 
The most frequently reported TEAE in the BXCL501 30 µg, 60 µg, and 90 µg treatment groups 
was somnolence (56.3% [n=9], 60.0% [n=12], and 75.0% [n=3], respectively); placebo was 0%. 
All cases of somnolence were considered by the investigator to be mild in severity, with the 
exception of 1 subject (103-01-037) in the BXCL501 60 µg whose case was considered to be 
moderate in severity and not serious. 

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Hypotension was reported in only 3 subjects, of which 2 subjects were in the BXCL501 60 µg 
group (severity was mild in 1 subject and moderate in the other subject) and 1 subject was in the 
BXCL501 90 µg group (severity was mild). No syncope or falls were reported. 
In Study BXCL501-301 (schizophrenic population) and Study BXCL501-302 (bipolar disorder 
population) single doses up to 180 ug were administered with no serious adverse effects (see 
Section 6.4.1 and Section 6.4.2, respectively).
10.9.
Treatment Compliance
Drug accountability will be performed by site personnel and the drug administration compliance 
is expected to be 100%. 
10.10. 
Concomitant Medications 
All concomitant medications used (including over-the-counter medications and herbal and 
nutritional supplements) will be recorded in the source document and on the appropriate CRF. 
The medication name, dose, frequency, date, and indication for use must be recorded on the 
CRF. Medications and therapies that are considered necessary for the subject’s welfare and will 
not interfere with the response to the investigational product may be given at the discretion of the 
investigator. 
10.10.1.
Permitted Therapies
Concomitant medications, such as those used for the treatment of agitation, are allowed, with 
some potential restrictions (see Table 10.1). Other concomitant medications are allowed unless 
specifically prohibited (see Table 10.1), but should be limited to only those medications 
considered necessary. Smoking is allowed according to the site policies. 
Rescue Medication 
At the discretion of the investigator, rescue therapy may be initiated using standard of care 
treatment for acute agitation. The use of lorazepam is discouraged. When rescue administration 
occurs, the medication, time, dose, and indication must be clearly recorded as ‘For agitation’ in 
the CRF and source documents. 
Medications for Insomnia 
Benzodiazepines may be administered for insomnia. Administration may not occur sooner than 4 
hours after dosing of study treatment and the indication (insomnia) must be clearly recorded in 
the CRF and source documents. 
10.10.2. 
Prohibited Therapies 
A list of prohibited medications prior to and after dosing is provided in Table 10.1. 
Patients may receive concomitant medications listed in Table 10.1 on a routine daily, or as 
needed basis. Therefore, to ensure patient safety and allow any sedative or calming effect of the 
listed prohibited medication to become apparent, investigators should make every attempt to 
allow 4 hours to elapse after a prohibited medication to assess the agitation, it’s improvement, 
continuation or worsening. 

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If the subject’s agitation is not improving, continuing or worsening, after 2 hours of receiving a 
prohibited medication, investigators may proceed with the Pre-dose assessments. For these 
subjects, 4 hours may not have elapsed and this would not be a protocol violation.  
Table 10.1: 
List of Prohibited Medications Prior to and After Investigational Product 
Dosing 
If possible, within 4 hours prior to dosing of the investigational product the following 
medications should not be administered
Sedative/hypnotics
Barbiturates
Anxiolytics (including benzodiazepines)  
Antihistamines (e.g., diphenhydramine) 
Sedating antidepressants (mirtazapine, trazodone)
Triptans (e.g., sumatriptan) or other serotonin-agonist medications for migraine
Opioids
The following medications are prohibited from the time the episode of agitation is 
identified until 4 hours post-dose, unless clinically indicated
Antiarrhythmics
Antibiotics/antifungals/antivirals  
Anticholinergics  
Anticonvulsants
Antihypertensives (specifically other alpha-adrenergic medications including clonidine, 
guanfacine, and prazosin)
Anxiolytics or sedative-hypnotics  
Centrally acting calcium antagonist 
Cholinomimetics  
Triptans or other migraine-serotonin receptor agonists 
Opioids
At the discretion of the investigator antihypertensives or other medications may be held on the 
day of dosing to ensure and maintain subject safety before and after investigational product 
dosing.
When possible, antipsychotics should not be administered within 4 hours prior to dosing of the 
investigational product.

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11.
STUDY PROCEDURES
Subjects or their LAR will provide written informed consent (in person or remotely) before any 
study-related procedures are initiated, including the cessation of prohibited concomitant therapy. 
11.1. 
Screening (W
Before the First Dose of Investigational 
Product) 
The Screening Visit may be conducted over more than one day; however, all procedures must be 
completed prior to subject randomization and within 45 days of signing informed consent. 
Screen Failures: Subjects who fail inclusion and/or exclusion criteria may be rescreened for the 
study at discretion of the investigator. Subjects may only be rescreened one time. 
The following procedures will be performed at Screening (refer to the Schedule of Events in 
Table 3.1):
 Obtain written informed consent from subject or LAR, if applicable. Symptoms, 
understanding of study, and appropriateness must be documented in source. No study 
procedures may be performed prior to completion of the ICF process. 
 Review inclusion and exclusion criteria 
 Collect demographic information 
 Record resting and orthostatic vital signs 
 Record medical history, including prior therapies (e.g., prescription and non-prescription 
medications, if known onset and type of dementia) 
 Record concomitant medication use 
 Physical examination (including weight and height) 
 12-lead ECG with rhythm strip 
 Collect blood and urine samples for clinical laboratory tests (hematology, clinical 
chemistry, urinalysis) 
 Urine pregnancy test 
 UDS (note: UDS will be re-collected if more than 21 days have passed since the initial 
collection at the screening visit) 
 UTI 
 Johns Hopkins Fall Risk Assessment 
 ADAS-Cog 12 
 MMSE 
 PEC
 PAS
 C-SSRS
 CGI-S 
Screening assessments to be performed within 45 days before the first dose of investigational 
product; the assessments may be conducted over more than one day during the Screening period. 

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If a subject does not become agitated within the 45-day window, the subject is considered a 
screen failure. However, that subject can be rescreened one additional time at the discretion of 
the investigator. 
11.2.
Pre-Dose (within 90 Minutes Before the Dose of Investigational 
Product) 
The following procedures will be performed at Pre-dose (see Table 3.1):
Review inclusion and exclusion criteria (before the first dose of study drug only, not at 
subsequent doses) 
Record resting and orthostatic vital signs 
Record concomitant medication use 
12-lead ECG with rhythm strip
Pulse oximetry
MMSE (before the first dose of study drug only, not at subsequent doses) 
 PEC 
 PAS 
 ACES 
 CGI-S 
 Record agitation behaviors 
 Sublingual (SL) assessment 
 PK sampling 
Randomization criteria prior to dosing the first dose of study drug are: 
1. 
 
2. Subjects who are judged to be clinically agitated at pre-
the 4 items (aberrant vocalization, motor agitation, aggressiveness, and resisting care) 
comprising the Pittsburgh Agitation Scale (PAS). 
Criterion for dosing study drug for subsequent episodes of agitation: 
. 
11.3. 
Post-Dose Assessments (through post dose day 3) 
The following are the post-dose assessments; the specific timepoints are provided in Table 3.1.
 ECG with rhythm strip 
 Pulse oximetry
 Resting vital signs 
 Orthostatic vital signs 
 Physical examination (including weight) 
 MMSE 

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 PEC
PAS
ACES
CGI-S 
CGI-I 
C-SSRS
 Record agitation behaviors 
 ADAS-Cog 12 (collected on day 3 only if day 83 or day 84 is the last dose day) 
 Sublingual (SL) assessment 
 PK sampling 
 Safety laboratory assessments 
 Drug Likability Scales 
 Likability Questionnaire 
 Record concomitant medications 
 Record adverse events 
When the Day2/24 hr and predose visits will occur on the same day, the Day 2/24 hrs 
assessments (see Appendix 1) will serve as the predose assessments as long as the subject is 
dosed within 90 minutes of the collection of the Day2/24 hrs assessments. Every effort should be 
made to collect the PEC, PAS, ACES, and CGI-S within 15 minutes prior to dosing. All post-
dose efficacy assessments should be conducted prior to any other assessments at each time point. 
If subsequent dosing cannot occur within 90 minutes of the collection of the Day2/24 hr 
assessments, all predose assessments must be recollected as per protocol.  
The exception are those assessments (see Appendix 1), as these must be completed as part of the 
predose assessments before every dose.  
Assessments done at Day 2/24 hrs that are also being used as predose assessments should be 
captured as the Day 2/24 hrs assessment data and as the predose data. 
 
Weekly Assessments (During the 12 Week [d
ET] Treatment 
Period) 
Routine assessments will be performed on a weekly basis during the course of the 12 Week (84 
days) study and are noted below (see Table 3.2 for specific details). If a dose is administered on 
the same day or within the window of a scheduled weekly assessment, all dosing assessments 
will be performed in lieu of the scheduled weekly assessment. If a 24 hour post-dose assessment 
coincides with a weekly assessment, then the post-dose 24 hour assessment will take precedence. 
Safety laboratory assessments should be conducted if they are scheduled as part of the weekly 
visit even though they are not part of the 24 hour post-dose assessments. 
 ECG with rhythm strip 
 Resting vital signs 
 Orthostatic vital signs 

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 C-SSRS
MMSE
Physical exam (including body weight) 
Safety laboratory assessments
Sublingual (SL) assessment
Record concomitant medications
 Record adverse events 
11.5. 
Premature Discontinuation (Withdrawal)  
As provided in Section 9.2, a subject can voluntarily withdraw from participation in the study or 
can be withdrawn from the study at the discretion of the investigator. 
Whenever possible and reasonable, evaluations that were scheduled for study completion (as 
listed above in Table 3.2 should be performed at the time of premature discontinuation of dosing. 
The Investigator should make every effort should be made to encourage the subject to follow all 
procedures outlined in the protocol including self-administration of the film. After 3 attempts if 
the subject still refuses, that subject will be discontinued from the study. 

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12.
STUDY ASSESSMENTS
12.1.
Efficacy 
The effect of study drug will be evaluated using several validated instruments as described 
below. All rating assessments will be performed by trained research staff.
12.1.1. 
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 
(absence of agitation) to 35 (extremely severe) (Montoya, Valladares et al. 2011). 
12.1.2. 
Pittsburgh Agitation Scale (PAS) 
The Pittsburgh 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 
4 behavior groups observed (using a 0 to 4-point scale) in the patient, Aberrant Vocalization, 
Motor Agitation, Aggressiveness, Resting Care (Rosen et al, 1994). 
12.1.3. 
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 
(Ono, 2007). 
 
CGI-S and CGI-I 
Both CGI-I and CGI-S will be focused on the severity of agitation rather than the severity of the 
overall illness of dementia. 
 CGI-S 
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 = Mildly symptomatic-low level of symptoms-little interference in social functioning 
3 = Moderately symptomatic-some prominent symptoms-some interference in functioning 
4 = Severely symptomatic- very marked symptoms make it difficult for patients to engage with 
others  
 CGI-I 
Drug response on agitation will be evaluated by the Clinical Global Impressions – Improvement 
(CGI-I) which is performed after dosing. Please rate the current level of agitation relative his/her 

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level of agitation before administration of the study drug using the following rating scores. A 
score of "0" indicates an assessment was not conducted. 
The CGI-I scores range from 1 to 7: 
1=very much improved, 
2=much improved, 
3=minimally improved, 
4=no change, 
5=minimally worse, 
6=much worse, 
7=very much worse 
12.1.5. 
Drug Likability Scale 
After dosing with the study drug, subjects will assess their preference of the study drug by 
answering the statements "I like the taste of the medication” and “The medication is acceptable” 
using a 5-level Likert scale shown below: 
• Strongly disagree  
• Disagree  
• Neither agree nor disagree  
• Agree  
• Strongly agree  
12.1.6. 
Drug Likability Questionnaire
Subjects will respond to open-ended questions regarding their experience. Additional comments 
about aftertaste, smell, dissolve time, etc. will be asked as Yes/No questions with Yes responses 
prompting an explanation field. 
12.2. 
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 will characterize subject’s dementia (DSM-5 Major Neurocognitive disorder) in 
terms of cognitive and functional impairment.
12.2.1.
International Psychogeriatric Association Criteria for Agitation 
Inclusion criterion #4 for this study is: subjects are expected to exhibit behaviors that are 
congruent with the International Psychogeriatric Association (IPA) criteria for agitation 
representing a change from the subject’s usual behavior. The process and the criteria for 
agitation developed by the IPA are explained below. 
The IPA formed an Agitation Definition Work Group (ADWG) to develop a provisional 
consensus definition of agitation in patients with cognitive disorders that can be applied in 
epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, 

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and neurobiological studies. A consensus definition will facilitate communication and cross-
study comparison and may have regulatory applications in drug development programs. The 
ADWG conducted a broadly inclusive process, involving the IPA and its affiliate members, 
employing electronic means of participant engagement, holding a face-to-face meeting with 
international representation, and using survey-based methods. The ADWG was made up of the 
IPA leadership and other stakeholders interested in the neuropsychiatric aspects of AD and other 
disorders. The ADWG implemented a transparent process that included nearly 1,000 survey 
respondents and engaged the memberships of the IPA, IPA affiliates, and other organizations 
involved in the care and research of neuropsychiatric disorders in patients with cognitive 
impairment. 
A consensus definition of agitation was developed and the criteria are as follows: 
Agitation was defined broadly as: (1) occurring in patients with a cognitive impairment or 
dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting 
excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors 
that cause excess disability and are not solely attributable to another disorder (psychiatric, 
medical, or substance-related). A majority of the respondents rated all surveyed elements of the 
definition as “strongly agree” or “somewhat agree” (68–88% across elements). A majority of the 
respondents agreed that the definition is appropriate for clinical and research applications 
(Cummings et al, 2015). 
12.2.2. 
MMSE 
The Folstein Mini-Mental State Exam (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. The maximum total points on this test is 30. Table 12.1 provides an 
interpretation of MMSE scores.
Patients in this study will have score of 15 to 23 on the MMSE at Screening and at Pre-dose (see 
inclusion criterion #5)

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Table 12.1: 
Interpretation of Mini-Mental State Examination Scores 
Score 
Degree of 
Impairment
Formal Psychometric Assessment
Day-to-Day Functioning
25-30
Questionably 
significant 
If clinical signs of cognitive 
impairment are present, formal 
assessment of cognition may be 
valuable.
May have clinically significant 
but mild deficits. Likely to affect 
only most demanding activities of 
daily living. 
20-25
Mild
Formal assessment may be helpful to 
better determine pattern and extent 
of deficits.
Significant effect. May require 
some supervision, support and 
assistance.
10-20 
Moderate
Formal assessment may be helpful if 
there are specific clinical indications.
Clear impairment. May require 
24-hour supervision.
0-10
Severe
Patient not likely to be testable.
Marked impairment. Likely to 
require 24-hour supervision and 
assistance with activities of daily 
living. 
Source: Folstein MF, Folstein SE, McHugh PR: “Mini-mental state: A practical method for grading the cognitive 
state of patients for the clinician.” J Psychiatr Res 1975 Nov;12(3):189-98. 
12.2.3. 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 12  
The Alzheimer’s Disease Assessment Scale - Cognitive Subscale 12 (ADAS-Cog) was 
developed in the 1980s to assess the level of cognitive dysfunction in AD.  Although the 
ADAS-Cog was designed for people with AD, the ADAS-Cog has also been used as an outcome 
measure for studies of interventions in people with MCI.  It is also used for assessing the efficacy 
of antidementia treatments (Kueper et al., 2018; Skinner et al., 2012). The cognitive subscale of 
the original ADAS-Cog includes tasks that include both subject-completed tests and rater-based 
assessments. Together these tasks assess the cognitive domains of memory, language, 
orientation and praxis. 
The ADAS-Cog12 includes the following: Word Recall, Naming Objects and Fingers, Following 
Commands, Delayed Word Recall, Constructional Praxis, Ideational Praxis, Orientation, Word 
Recognition, Remembering Test Directions, Spoken Language, Comprehension, and Word 
Finding Difficulty (Kueper et al., 2018; Schafer et al., 2015). 
12.3. 
Pharmacokinetics 
Blood samples (4 mL) for PK analysis will be collected at pre-dose, and at 1, 2, 4, and 8 hours 
after the first dose and fifth dose of study drug only. However, if the investigator documents it is 
not appropriate to collect a sample from the subject (e.g., inability to access a venous site to 
collect a blood sample due to psychomotor agitation, subject refusal, subject’s current physical 
condition) at any of the scheduled timepoints, this will not result in the ineligibility of the 
subject’s participation, should not result in early termination nor will be considered a protocol 
deviation. All PK collections will have a window of ± 10 minutes post-dose. All PK sampling 
will occur only after all other assessments at that timepoint are conducted (see Table 3.1). 
The plasma concentration-time data will be analyzed by population PK methods. The sparse PK 
data obtained in this study will be added to the popPK model that has been developed for the 
drug, to update the model and determine exposure measures for this study. Additional analysis, 

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such as exposure-response analysis may be conducted based on available data. The methods for 
and results of these analyses will be reportedly separately, and a summary may be included in the 
CSR for this study. 
12.3.1. 
Sample Collection & Processing 
Details of the sample process will be provided in a PK sample manual, but it is envisioned to be 
the following process: 
 Blood samples will be collected in 4 mL vacutainer tubes containing dipotassium 
ethylenediaminetetraacetic acid (K2EDTA).
 The time and date of the collection of each blood sample will be recorded. 
 After the blood sample has been drawn into the vacutainer tube, it will be gently inverted 
at least 8 times, permitting the blood specimen to mix with the anticoagulant and avoid 
clotting of the sample. 
 Keep the tubes on ice until the blood samples can be centrifuged. Within 15 minutes of 
collection, centrifuge blood samples at approximately 1500 g for 15 minutes at 
approximately 4°C. 
 Labels will contain the following information: study number, subject number, study day, 
time point of sample collection (e.g., 2 hours post-dose), and aliquot/matrix (e.g., plasma 
primary aliquot or plasma secondary aliquot). Harvested plasma samples will be quick 
frozen over dry ice immediately. 
12.3.2. 
Sample Storage 
Plasma samples will be placed in a storage freezer at -70°C to -80°C or on dry ice within 
60 minutes of the blood collection. Samples should be placed in a -70°C to -80°C freezer until 
they are shipped to the bioanalytical laboratory. Freezers set at -20°C can also be used for a short 
period of time (maximum 1 month) until they must be shipped to the bioanalytical laboratory. 
12.3.3. 
Sample Shipment 
Prior to shipment, the samples will be appropriately packed into a Styrofoam cooler containing 
dry ice. 
 Sufficient dry ice will be added to ensure that the samples will remain frozen for at least 
24 hours for local shipments and for at least 72 hours for remote shipments. 
 Samples will be shipped in two aliquots. The second set will be shipped once the status of 
the first set has been verified.
 The site staff will maintain an inventory of the samples that are to be shipped to the 
bioanalytical laboratory, including the name of the study drug, protocol number, and the 
subject numbers and samples included in the shipment. A copy of the inventory will 
accompany the frozen PK samples. 
 The samples will be tracked to ensure arrival in a safe and timely manner. 

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 Samples will be shipped to: 
Northeast Bioanalytical Laboratories LLC 
925 Sherman Ave 
Hamden, CT 06514 
Tel: 203-361-3768 
Cell: 203-606-8840 
 
Analytical Procedures 
 
Bioanalytical Sample Analyses 
A validated liquid chromatography-tandem mass spectrometry procedure will be used to measure 
plasma concentrations of dexmedetomidine (BXCL501) and relevant metabolites. Samples from 
subjects who have at least 1 post-dose sample will be analyzed.
The bioanalytical report of the assay of the samples will be included in the final report. 
Analytical results will be presented in tabular form in the final report and chromatographic and 
derived data will also be provided. Additionally, accuracy, precision, and linearity data for each 
standard curve and all quality control samples may be presented. Representative chromatograms 
and standard curve graphs may be included. A bioanalytical sample analysis report with quality 
assurance statement will be included in the final clinical study report (CSR). Copies of serially 
selected sample chromatograms for 20% of all samples may be included in the final report. 
12.5. 
Safety 
During the study, AEs, clinical laboratory tests, 12-lead ECG with rhythm strip, pulse oximetry, 
and vital signs will be monitored for tolerability assessment. All observed and volunteered AEs 
will be recorded. The relationship of AEs to the study drug will be graded as not related, 
unlikely/remotely related, possibly related, probably related or definitely related by the 
investigators. Vital signs including SBP, DBP, HR, along with orthostatic vital signs will be 
monitored. Any abnormal clinically significant (investigator determined) vital sign measurement, 
clinical laboratory test, physical examination finding, or ECG parameter will be repeated until 
the value returns to baseline (or within normal limits) or the investigator deems the abnormality 
to be of no clinical significance.
12.5.1. 
Adverse Events 
12.5.1.1. Adverse Event Definitions 
An 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.
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. Worsening of a 
preexisting condition is considered an AE. 

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An expected AE is one for which the nature or severity is consistent with the known AE profile 
of the product. For an investigational drug, the known information is contained in the 
investigator brochure. For a marketed drug, the known information is in the current package 
insert. 
An unexpected AE is one for which the specificity or severity is not consistent with the current 
investigator brochure or package insert. For example, hepatic necrosis would be unexpected 
(greater severity) if the investigator brochure or package insert only listed elevated hepatic 
enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (greater specificity) if the investigator brochure or package insert only listed cerebral 
vascular accidents.
Furthermore, reports that add significant information on specificity or severity of a known, 
already documented adverse reaction constitute unexpected AEs. Examples include acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
and hepatitis with a first occurrence of fulminate hepatitis.
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life threatening
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity
 Is a congenital anomaly 
 Is an important medical event 
Medical and scientific judgment should be used in deciding whether it is appropriate to consider 
other situations serious, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent another of the outcomes listed in the definition previously. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
An elective hospital admission to treat a condition present before exposure to the study drug or a 
hospital admission for a diagnostic evaluation of an AE does not qualify the condition or event as 
an SAE. A newly diagnosed pregnancy in a subject who has received a study drug is not 
considered an SAE unless it is suspected that the study drug interacted with a contraceptive 
method and led to the pregnancy; however, the medical monitor should be made aware of a 
newly diagnosed pregnancy as soon as possible after site notification. A congenital anomaly in 
an infant born to a mother who was exposed to the study drug during pregnancy is an SAE. 
12.5.1.2. Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the CRF and 
reported to the medical monitor. Serious adverse events and AEs will be collected after the 
administration of the first dose of investigational product, after all subsequent dose 
administrations as well as throughout the study. 

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At each visit, subjects will be asked for any medically related changes in their well-being. They 
will also be asked if they have had any accidents, used any new medications, or changed 
concomitant medication regimens (both prescription and over-the-counter medications). In 
addition to subject observations, AEs will be documented based on all available source data (e.g., 
clinical laboratory values, physical examination findings, ECG changes, etc) or other documents 
that are relevant to subject safety. 
12.5.1.3. Reporting Adverse Events
All AEs reported or observed during the study will be recorded on the AE page of the CRF. 
Information to be collected includes drug treatment, type of event, time of onset, dose, 
investigator-specified assessment of severity and relationship to study drug, time of resolution of 
the event, seriousness, as well as any required treatment or evaluations, and outcome. Adverse 
events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. All AEs will be 
followed to adequate resolution. A recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
The investigator or designee must report any AE that meets the criteria for an SAE 
(Section 12.5.1.1) to BioXcel’s vendor designee within 24 hours of first becoming aware of the 
event by e-mail or fax using an SAE report form. At the time of first notification, the investigator 
or designee should provide at a minimum the following information if available: 
 Investigator information (name, phone, fax, e-mail) 
 Protocol number 
 Subject’s study identification and initials
 Subject’s date of birth 
 Date of dose of study drug 
 Time and date of occurrence of the event 
 A brief description of the event, outcome to date, any actions taken, and, if available, the 
relationship of the AE to the study drug and study conduct. 
. Any missing or additional relevant information about the SAE should be provided in a written 
follow-up SAE report form. The investigator should also ensure that any additional information 
requested about the event (e.g., hospital reports, autopsy reports) is provided as soon as it is 
available. 
The investigator is required to comply with applicable regulations (including local laws and 
guidance) regarding the notification of the institutional review board (IRB). 
SAEs will be reported to BioXcel's vendor designee (s) as per the current Safety Monitoring Plan 
associated with this study. 
12.5.1.3.1. Assessment of Severity 
The severity or intensity of an AE refers to the extent to which it affects the subject’s daily 
activities. Severity will be rated as mild, moderate, or severe using the following criteria: 

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Mild:
Is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate: 
Is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent 
risk of harm to the subject.
Severe:
Interrupts usual activities of daily living, significantly affects 
clinical status, or may require intensive therapeutic intervention 
Changes in the severity of an AE should be documented to allow assessment of the duration of 
the event at each level of intensity to be performed. Serious AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
12.5.1.3.2. Assessment of Relationship 
The investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process but is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Not related:
An AE with enough evidence to accept that there is no causal 
relationship to administration of study drug (e.g., no temporal 
relationship because the study drug was administered after the 
onset of the event, an investigation shows that study drug was 
not administered, another cause was proven.)
Unlikely/Remotely 
related:
An AE, including a clinical laboratory test abnormality, with a 
temporal relationship to administration of study drug that makes 
a causal relationship improbable and in which other drugs, 
events, or underlying disease provide plausible explanations.
Possibly related:
An AE with a reasonable time sequence to administration of 
study drug but that could also be explained by concurrent 
disease or other drugs or events. Information on drug withdrawal 
may be lacking or unclear.
Probably related: 
An AE with a reasonable time temporal sequence from 
administration of the study drug; or the AE follows a known 
pattern of or response to the study drug; or an alternative 
explanation (e.g., concomitant disease, environment factors, 
and/or concomitant medications) is less likely than attribution to 
the study drug; or the AE diminishes or disappears upon 
cessation of study drug. 
Definitely Related:
An AE occurring in a plausible time relationship to 
administration of study drug and that cannot be explained by a 
concurrent disease or other drugs or events. The response to 
withdrawal of the drug (dechallenge) is clinically reasonable. 

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12.5.1.3.3. Definition of Adverse Event Outcome at the Time of Last Observation 
The AE outcome at the time of last observation will be classified as “resolved”, “resolved with 
sequelae”, “ongoing”, “death”, “other”, or “unknown”. 
“Death” should only be selected as an outcome when the AE resulted in death. If more than 1 AE 
is possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE. Although “death” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
 Follow-up of Adverse Events
Any AE will be followed (up to a maximum of 30 days after dosing with study drug) to a 
satisfactory resolution or until the investigator deems the event to be chronic or not clinically 
significant or the subject to be stable. All findings relevant to the final outcome of an AE must be 
reported in the subject’s medical record and recorded on the appropriate CRF. 
12.5.2. 
Johns Hopkins Fall Risk Assessment Tool 
The Johns Hopkins Fall Risk Assessment Tool (Acute Care Tool) is a validated risk stratification 
tool to facilitate early detection of risk of falling in adult inpatients by assessing various 
point-based criteria to derive a total risk score.  
The assessment will be conducted at the Screening visit (see Table 3.1). 
12.5.3. 
C-SSRS 
The Columbia Suicide Severity Rating Scale (C-SSRS) (Oquendo, 2003) is a suicidal ideation 
rating scale. The scale identifies behaviors and thoughts that are associated with an increased risk 
of suicidal actions in the future. The C-SSRS assessment will be conducted at Screening 
(see Table 3.1 and at other timepoints listed in Table 3.2). 
 
Laboratory Safety Assessments  
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Events tables (Table 3.1 and Table 3.2). Laboratory assessments will be performed 
by a central laboratory. NOTE: In cases where repeat laboratory tests may be required to confirm 
eligibility prior to dosing, a local laboratory may be used to obtain repeat test results.  
Hematology:
Screening and weekly timepoints 
Consists of complete blood count (hemoglobin, hematocrit, 
white blood cell count with differential, red blood cell 
count, and platelet count)
Serum chemistry: 
Screening and weekly timepoints 
Includes blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase (serum 
glutamic-oxaloacetic transaminase), alanine 
aminotransferase (serum glutamic pyruvic transaminase), 
glucose, albumin, total protein, and electrolytes (sodium, 
chloride, potassium, and bicarbonate)
Urinalysis: 
Screening and weekly timepoints 

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Includes pH, specific gravity, protein, glucose, ketones, 
bilirubin, blood, nitrites, leukocytes, urobilinogen, 
microscopic urine analysis if dipstick positive
Urine pregnancy test: 
Screening
Women of child-bearing potential only 
Urine drug screen:
Screening
Cocaine, amphetamine, phencyclidine, benzodiazepines, 
marijuana. (Note; marijuana positive is allowed provided 
subject is not moderately to severely dependent, 
benzodiazepine positive are allowed if prescribed) 
12.5.5. 
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 time points specified in the schedule of events. Measurements should be made at least 
1 minute apart using the same arm at each visit.
Orthostatic measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP) and 
heart rate (HR) will be done with subjects standing and measurements taken after 1, 3, and 5 
minutes, per Centers for Disease Control and Prevention guidelines for elderly at Screening, at 
Pre-dose, and at 1, 2, 4, 8, and 24 (Day 2) hours post-dose, and on Day 3 post-dose.  
A change from supine to standing of 20 mmHg SBP or 10 mmHg DBP must be repeated. If any 
one of the three orthostatic BP readings (1, 3 and/or 5 mins) show a decrease, from supine to 
standing, of 20 mmHg SBP or 10 mmHg DBP, the entire process needs to be repeated, which 
includes repeating the resting and orthostatic BPs. 
In non-ambulatory subjects, those who are unable to stand, orthostatic vital sign measurements 
will not be taken. This will not constitute a protocol deviation.  
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 timepoints. 
12.5.6.
Electrocardiogram
A 12-lead ECG with rhythm strip will be performed at Screening, Pre-dose, Post-dose, and at 
specific timepoints during the 12 week treatment period. Details are provided in Table 3.1 and 
Table 3.2. 
Each site will be provided with an ECG machine. The ECG data (triplicate ECGs are to be 
obtained, approximately 1-3 minutes apart from each site will be sent to a central specialist for 
further assessment. The Principal Investigator must review the ECG to ensure eligibility and 
safety of the subject. 
12.5.7.
Physical Examination 
A standard physical examination will be performed and 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.

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Physical examinations will be performed at Screening Table 3.1 and at other timepoints listed in 
Table 3.2. 
12.5.8. 
Concomitant Medications 
Concomitant medications will be reviewed and documented throughout the entire 12 week study 
period. Please refer to Section 10.10 for more details regarding permitted and prohibited 
concomitant medications. 

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13.
STATISTICAL METHODS
13.1.
General Considerations
A statistical analysis plan (SAP) that describes the details of the analyses to be conducted will be 
finalized before database lock.
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum 
values for continuous variables, and number and percentage of subjects in each category for 
categorical variables) will be provided by treatment group for evaluated variables.  
All statistical tests and confidence intervals, unless stated otherwise, are 2-sided and will be set 
13.2.
Analysis Populations
The following analysis populations are planned: 
 Safety Population: All subjects receiving at least 1 dose of study drug, with subjects 
classified according to the drug actually received. 
 Full Analysis Set: All subjects who take any study medication and who had both baseline 
and at least one efficacy assessment after dosing. 
13.3. 
Statistical Analyses 
Continuous variables will be summarized by treatment using descriptive statistics (n, mean, 
median, standard deviation, minimum, and maximum). For categorical variables, frequencies and 
percentages will be presented by treatment. Baseline is defined as the last observation prior to 
initiation of study drug. Missing data is not anticipated at the 2 hour primary time point. Details 
of the statistical analyses will be provided in the SAP, which will be finalized prior to database 
lock. 
13.3.1.
Subject Disposition and Demographic Characteristics
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. 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.
Demographics and baseline characteristics, including age, sex, race, weight, height, and body 
mass index, will be summarized by treatment for the Safety Population. 
13.3.2.
Efficacy Analyses 
Efficacy analyses will use data from the full analysis set (FAS) as the target population, defined 
as all subjects who take any study medication and who had both baseline and at least one 
efficacy assessment after dosing. Change from baseline (pre-dose) in the PEC at 2 hours post-
dose for the first treated agitation episode will be considered primary. 
Efficacy analyses for measures assessed at specific scheduled time points will evaluate the 
change from baseline using a mixed model repeated measures (MMRM).  

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Additional details regarding analysis models, control for multiplicity and sensitivity analyses in 
the event of missing data associated with intercurrent events of specific types will be included in 
the statistical analysis plan. 
13.3.2.1. Primary Efficacy Analysis 
The change from baseline in PEC total score at 2 hours post-dose for the first treated episode of 
agitation constitutes the primary endpoint for this study. Table 13.1 provides the information for 
the four estimand attributes needed for the primary efficacy analysis. 
Table 13.1: 
Estimand Attributes for the Primary Efficacy Analysis 
Estimand attribute
Description of attribute
Target population
FAS population - All patients who take any study 
medication and who had both baseline and at least one 
dose of study drug.
Primary endpoint
Absolute change from baseline in the total PEC score at 
2 hours post-dose for the first treated episode of agitation.
Handling of intercurrent events
All values collected after the use of rescue treatment and 
withdrawal from study will be used in the analysis 
(treatment policy strategy). 
Population-level summary
Difference between dose-specific treatment arm and 
placebo arm in mean change from baseline in the total PEC 
at 2 hours using all measurements from baseline through 
4 hours.
Abbreviations: FAS = Full Analysis Set; PEC = Positive and Negative Syndrome Scale – Excited Component  
The null and alternative hypotheses to be tested for the primary endpoint are stated as 
H01: 
BXCL501_60
PBO
BXCL501_60
PBO 
BXCL501_40
PBO and 
HA2: 
BXCL501_40
PBO
BXCL501_60 denotes the change from baseline in the PEC at 
2 hours post-
BXCL501_40 denotes the change from baseline in 
the PEC at 2 hours post-
PBO denotes the change from 
baseline in the PEC at 2 hours post-dose in the placebo group. These hypotheses will be tested 
using a mixed model repeated measures (MMRM) model. To account for the testing of two 
hypotheses, the two-sided significance level for each test will be determined using the 
Bonferroni correction with each hypothesis tested at a significance level of 0.025. 
The MMRM will include the change from baseline in the PEC at 30 minutes, 1 hour, 2 hours, 
and 4 hours post-dose as the outcome and the baseline PEC, treatment group, antipsychotic use 
(stratification factor), visit number, and a treatment group by visit number interaction term as 
covariates. 
The model will be fit using an unstructured covariance matrix with the Kenward-Rogers 
adjustment for the degrees of freedom. As the change from baseline in PEC score is only 
measured at 30 minutes, 1 hour, 2 hours and 4 hours, the covariance structure includes a total of 
10 parameters making the likelihood that the model fails to converge low. In all prior studies of 
BXCL501 there have been few missing data points in the two-hour assessment window; 
however, methods to address missing data are proposed as part of the sensitivity analyses. 

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In the event that the model fails to converge with an unstructured covariance matrix, the 
following covariance structures will be applied, in order, until convergence is reached: 
heterogenous Toeplitz structure, Toeplitz structure, auto-regressive of order 1 (AR(1)), and 
compound symmetry structure. For the alternative covariance structures, the sandwich estimator 
will be used to obtain the estimates of the standard error and the Kenward-Rogers adjustment for 
degrees of freedom will not be applicable. If convergence proves to be a problem and an 
alternative covariance structure is needed there may be an inflation of type I error. To address 
this, the methods proposed in Lu and Mehrotra (2009) will be used as well with the Fisher 
scoring algorithm being used to obtain the initial values of the covariance parameters. 
The estimated mean difference between the groups treated with either 40 µg or 60 µg BXCL501 
and the placebo group in change from baseline in the PEC score will be estimated at 2 hours. 
13.3.2.2. Key Secondary Efficacy Endpoints 
Key secondary efficacy endpoints are: 
 PEC change from baseline at 1 hour post-dose of study treatment for the first episode of 
agitation (measures initial efficacy)
 PEC change from baseline at 30 minutes post-dose of study treatment for the first episode 
of agitation (measures initial efficacy) 
The attributes for the estimands of the key secondary endpoints of PEC change from baseline at 
1 hour post-dose for the first episode of agitation and the PEC change from baseline at 
30 minutes post-dose for the first episode of agitation are provided in Table 13.2. 
Table 13.2: 
Estimand Attributes for the Key Secondary Analyses of Change from 
Baseline in total PEC score at 1 hour and at 30 minutes 
Estimand attribute
Description of attribute 
Target population
FAS population - All patients who take any study 
medication and who had both baseline and at least one 
dose of study drug.
Primary endpoint
Absolute change from baseline in the total PEC score at 1 
hour or at 30 minutes.
Handling of intercurrent events
All values collected after the use of rescue treatment and 
withdrawal from study will be used in the analysis 
(treatment policy strategy). 
Population-level summary
Difference between dose-specific treatment arm and 
placebo arm in mean change from baseline in the total PEC 
score at 1 hour or at 30 minutes using all measurements 
from baseline through 4 hours. 
Abbreviations: FAS = Full Analysis Set; PEC = Positive and Negative Syndrome Scale – Excited Component 
The null and alternative hypotheses to be tested for the two key secondary endpoints listed above 
are similar to those for the primary endpoint, with the timepoint for testing being 1 hour post-
dose for the first key secondary endpoint and 30 minutes post-dose for the second key secondary 
endpoint. These hypotheses will be tested using the MMRM model described for the primary 
analysis. 

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The endpoints, in the order to be tested, are as follows:  
1. PEC change from baseline to 1 hour for the first treated episode of agitation.
2. PEC change from baseline to 30 minutes for the first treated episode of agitation. 
The fixed-sequence method will be used to adjust for multiplicity and applied to each dose 
separately. If at any point in the testing, the significance level is greater than 0.025 for the 
comparison of interest, then all testing ceases for that dose level and the remaining p-values are 
reported as nominal levels. 
13.3.2.3. Continued Efficacy Endpoints 
The continued efficacy endpoints and a description of the proposed analysis approach are 
outlined below. 
• 
PEC change from pre-dose at 2 hours post-dose of study treatment for the last treated 
episode of agitation. This endpoint will be analyzed using the MMRM model that is used 
for the primary analysis. 
• 
PEC change from pre-dose at 2 hours post-dose of study treatment for all treated episodes 
of agitation. This is a multivariate endpoint consisting of the PEC change from pre-dose 
at 2 hours post-dose of study treatment for all treated episodes of agitation. The null 
hypothesis being tested is that there is no decline in treatment effect over all episodes of 
agitation. The model has been parametrized with the PEC change from pre-dose at 2 
hours post-dose for each treated episode of agitation as the outcome and the following 
covariates: baseline pre-dose PEC value for the treated episode, number of episodes, time 
(days) of the treated episode, trt_40 which is an indicator variable that is equal to 1 for all 
subjects in the BXCL 40 µg group and 0 otherwise, trt_60 which is an indicator variable 
that is equal to 1 for all subjects in the BXCL 60 µg group and 0 otherwise, and 
interaction term of time and trt_40, and an interaction term of time and trt_60. Details of 
the analysis approach will be provided the statistical analysis plan (SAP.) 
• 
Percentage of all treated episodes of agitation satisfying the definition of PEC responder, 
an episode with at least a 40% reduction in PEC total score from pre-dose at 2 hours post-
dose of study treatment will be analyzed using an ANCOVA model with percentage of 
episodes meeting the definition of PEC responder as the outcome, and treatment group 
and antipsychotic use (stratification factor) as covariates. A weighted least squares 
approach may also be used to account for the differing number of episodes across 
subjects. 
• 
Percentage of all treated episodes of agitation for which the PEC change from pre dose at 
2 hours post-dose of study treatment is a reduction of at least 5 points (measures 
continued efficacy) will be analyzed using an ANCOVA model with percentage of 
episodes meeting the definition of PEC responder as the outcome, and treatment group 
and antipsychotic use (stratification factor) as covariates. A weighted least squares 
approach may also be used to account for the differing number of episodes across 
subjects. 
• 
Average PEC change from pre-dose at 2 hours post-dose of study treatment over all 
treated episodes of agitation. This is a single endpoint which is computed based on the 

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averaging the change from pre-dose at 2 hours post dose of study treatment across all 
treated episodes. An ANCOVA model will be used for this analysis. The model will 
include the average change from pre-dose in PEC score at 2 hours over all episodes as the 
outcome, and treatment group and antipsychotic use (stratification factor) as covariates. 
A weighted least squares approach may also be used to account for the differing number 
of episodes across subjects. 
• 
Subgroup of subjects with at least two treated episodes of agitation with an endpoint of 
the PEC change from pre-dose at 2 hours post-dose of study treatment for the second 
episode of agitation. For this analysis, the MMRM model described for the primary 
analysis will be used. 
• 
Subgroup of subjects with at least three episodes of treated agitation with an endpoint of 
the PEC change from pre-dose at 2 hours post-dose of study treatment for the third 
episode of agitation. For this analysis, the MMRM model described for the primary 
analysis will be used. 
• 
Severity of each treated episode of agitation at pre-dose, as measured by PEC (measures 
continued efficacy) will be analyzed using a longitudinal mixed model with the outcome 
being the pre-dose PEC value at each episode. Time is defined as the time of the episode 
in study day (ranging from 1 to 84 days). The model will include an intercept as a random 
effect, treatment group as a class variable, antipsychotic use (stratification factor), and a 
time by treatment group interaction term as fixed effects. The model will be fit with no 
fixed effect intercept term. Under this model the null hypothesis that the slope measuring 
the rate of change of the pre dose PEC score across all treated episodes is zero will be 
tested.  Details of the analysis approach will be provided the statistical analysis plan 
(SAP.) 
• 
Frequency of treated episodes of agitation (measures continued efficacy). This is a single 
outcome defined as the number of treated episodes of agitation for each subject. It will be 
assessed with a Poisson model that includes treatment group and antipsychotic use 
(stratification factor) as covariates. The results will be summarized as an incidence rate 
ratio and the significance level for the test of the null hypothesis of no difference between 
each dose level and placebo will be obtained from the significance level for the test of 
each dose level versus placebo.  
• 
PEC change from pre-dose at 2 hours post-dose of study treatment at the last treated 
episode of agitation –PEC change from pre-dose at 2 hours post-dose of study treatment 
at the first treated episode of agitation. This is a single outcome. The goal of the proposed 
analysis is to determine if there is a change in treatment effect when comparing the first 
and last treated episodes. It is anticipated that there will not be a large difference between 
the treatment effect at the first and last treated episode for the groups receiving either 
BXCL501 40 µg or BXCL501 60 µg. The same result is anticipated for the placebo 
group as well. Thus, it is likely that this will provide a larger significance level with a 
result of failure to reject the null hypothesis. While this result does not demonstrate that 
the outcome is the same at the first and last treated episodes, this analysis will contribute 
to the body of evidence supporting continued efficacy. Details of the analysis approach 
will be provided the statistical analysis plan (SAP.) 

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 Other Secondary Efficacy Endpoints 
The methods that will be used to analyze each outcome will be as follows: 
 The number of PEC responders (patients who achieve at least a 40% reduction in PEC 
total score from pre-dose at 2 hours post-dose of study treatment) for the first treated 
episode of agitation will be analyzed using a stratified Mantel-Haenszel test stratified 
by antipsychotic use (stratification factor).  
 The change from baseline in PAS and CGI-S at 2 hours and the CGI-I at 2 hours 
post-dose for the first episode of agitation will be analyzed using an ANCOVA model 
with the change from baseline at 2 hours post-dose as the outcome, and baseline value 
of the outcome (used only for PAS and CGI-S), antipsychotic use (stratification factor), 
and treatment group as covariates. 
 The number of CGI-I responders (patients who achieve a CGI-I score of 1 or 2 at 
2 hours post-dose of study treatment) for the first episode of agitation will be analyzed 
using a stratified Mantel-Haenszel test, stratifying according to the stratification factor 
of antipsychotic use. 
 The average change in PAS and CGI-S at 2 hours post-dose over all treated episodes of 
agitation will be analyzed using an ANCOVA model with the average values of change 
in PAS or CGI-S across all episodes as the outcome, and treatment group and 
antipsychotic use (stratification factor) as covariates. 
 The average CGI-I at 2 hours post-dose over all treated episodes of agitation will be 
analyzed using an ANCOVA model with the average CGI-I across all episodes as the 
outcome, treatment group and antipsychotic use (stratification factor) as covariates. 
 The percentage of all treated episodes of agitation satisfying the definition of CGI-I 
responder will be analyzed using an ANCOVA model with treatment group and 
antipsychotic use (stratification factor) as covariates.
 Average PEC change from pre-dose at 1-hour post-dose of study treatment over all 
treated episodes of agitation will be analyzed using an ANCOVA model with treatment 
group and antipsychotic use (stratification factor) as covariates. 
 Average PEC change from pre-dose at 30 minutes post-dose of study treatment over all 
treated episodes of agitation will be analyzed using an ANCOVA model with treatment 
group and antipsychotic use (stratification factor) as covariates. 
 Change from screening in ADAS-Cog 12 at day 84 will be analyzed using a 
two-sample t-test. 
 The change from baseline in ACES scores at 2, 4, and 8 hours post-dose for the first 
episode of agitation, will be analyzed using an ANCOVA model with the change from 
baseline in ACES score as the outcome, and the baseline value of the outcome, 
antipsychotic use (stratification factor), and treatment group as covariates.
 Change from screening in MMSE at Day 28 and at Day 84 will be analyzed using a 
two-sample t-test. 
13.3.3. 
Safety and Tolerability Analyses 
Safety data analysis will be conducted on all subjects receiving at least 1 dose of study drug. The 
number and percentage of subjects experiencing 1 or more AEs will be summarized by 
treatment, relationship to study drug, and severity. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. Listings of subjects who 

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experience withdrawal due to an AE, SAEs and/or death will be presented. Laboratory 
parameters will be summarized by treatment using descriptive statistics and data listings of 
clinically significant abnormalities. Vital signs and ECG data will be summarized by changes 
from baseline values using descriptive statistics. 
Orthostatic assessments will follow the Centers for Disease Control and Prevention guidelines 
for the elderly (e.g., BP upon standing for 1, 3, and 5 minutes) 
(https://www.cdc.gov/steadi/pdf/Measuring_Orthostatic_Blood_Pressure-print.pdf). 
Results will be presented for first dose of study drug and for all doses of study drug.  
 
Sample Size Determination 
Approximately 150 subjects are anticipated to be enrolled. Assuming a standard deviation of 4 in 
change from baseline in the PEC at two hours post-dose and a two-sided two-sample t-test, 
150 subjects provides in excess of 90% power to detect a difference in mean PEC score of 
2.9 units or more, at the 0.025 alpha-level (adjusted for multiplicity of doses) for either dose 
versus placebo. 
A blinded sample size recalculation is currently planned when approximately 50% of the PEC 
total score data at 2 hours post initial dose are available. The pooled standard deviation of the 
change from baseline in PEC total score will be computed at each time point. The sample size 
will then be recalculated with the potential to adjust the sample size accordingly. Details of the 
sample size recalculation will be provided in the SAP. 

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STUDY CONDUCT
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel prior to the study, periodic monitoring visits, and strict data management procedures. 
 
Sponsor and Investigator Responsibilities 
 
Sponsor Responsibilities
The sponsor is obligated to conduct the study in accordance with strict ethical principles. The 
sponsor reserves the right to withdraw a subject from the study, to terminate participation of a 
study site at any time, or to discontinue the study. 
The sponsor agrees to provide the investigator with enough material and support to permit the 
investigator to conduct the study according to the study protocol. 
 
Investigator Responsibilities 
By signing the Investigator’s Agreement, the investigator indicates that he or she has carefully 
read the protocol, fully understands the requirements, and agrees to conduct the study in 
accordance with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including and in accordance with the April 
1996 International Council for Harmonisation (ICH) Guidance for Industry E6 Good Clinical 
Practice (GCP) and in agreement with the 1996 Version of the Declaration of Helsinki. While 
delegation of certain aspects of the study to sub-investigators and study coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing the study 
and for ensuring compliance with the protocol and all applicable regulations and guidelines. The 
investigator is responsible for maintaining a list of all persons that have been delegated study-
related responsibilities (e.g., sub-investigators and study coordinators) and his or her specific 
study-related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, study drugs, and their 
specific duties within the context of the study. Investigators are responsible for providing the 
sponsor with documentation of the qualifications, GCP training, and research experience for 
themselves and their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
 
Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site 
will not be authorized for study initiation until: 

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1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate informed consent. 
2. All GCP documents have been submitted to and approved by the sponsor or its designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting.
 
Study Documents 
All documentation and material provided by the sponsor for this study are to be retained in a 
secure location and treated as confidential material.
 
Good Clinical Practice Documents 
The GCP documents are listed below. 
 Signed original protocol (i.e., Investigator’s Agreement) 
 Curricula vitae of all investigators and sub-investigators 
 Name and address of the laboratories
List of laboratory reference ranges, and if available, a quality certificate
Signature Log/Delegation of Study-related Duties
 FDA Form 1572 
 Any other relevant GCP documents 
The GCP documents must be received from the investigator and reviewed and approved by the 
sponsor or designee before the study site can initiate the study and before the sponsor will 
authorize shipment of study drug to the study site. Copies of the investigator’s GCP documents 
must be retained at the study site in a secure location. Additional documents, including a copy of 
the protocol and applicable amendment(s), the study drug, CRF completion guidelines, copies of 
regulatory references, copies of IRB correspondence, and study drug accountability records 
should also be retained as part of the investigator’s GCP documents. It is the investigator’s 
responsibility to ensure that copies of all required GCP documents are organized, current, and 
available for inspection.
 
Case Report Forms 
By signing the Investigator’s Agreement, the investigator agrees to maintain accurate CRFs and 
source documentation as part of the case histories for all subjects who sign an informed consent 
form. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific CRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, CRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the CRF according to the 
completion guidelines provided by the sponsor or its designee. 

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The CRFs may be signed by the investigator or a sub-investigator. These signatures serve to 
attest that the information contained in the CRF is accurate and true. 
 
Source Documents 
All information recorded in the CRF must be supported by corresponding source documentation. 
Examples of acceptable source documentation include, but are not limited to, hospital records, 
clinic and office charts, laboratory notes, and recorded data from automated instruments, 
memoranda, and pharmacy dispensing records. 
During the study, select CRF data may be used as original data collection tools as long as a 
description of this documentation process is maintained in the investigator’s study files. Before 
the study starts, a list identifying any data to be recorded directly on the CRFs (i.e., no prior 
written or electronic record of data) and considered to be source data will be provided. 
 
Data Quality Control 
The sponsor and its designees will perform quality control checks on this clinical study. 
 
Monitoring Procedures 
The sponsor or designee will conduct site visits to monitor the study and ensure compliance with 
the protocol, GCP, and applicable regulations and guidelines. The assigned clinical research 
associate (CRA) will visit the investigator and study site at periodic intervals and maintain 
periodic communication. The investigator agrees to allow the CRA and other authorized sponsor 
personnel access. The CRA will maintain current personal knowledge of the study through 
observation, review of study records and source documentation, and discussion of the conduct of 
the study with the investigator and staff. While on site, the CRA will review:
Regulatory documents, directly comparing entries in the CRF with the source documents 
Consenting procedures 
AE procedures
 Storage and accountability of study drug and study materials 
The CRA will ask for clarification or correction of any noted inconsistencies. Procedures for 
correcting CRFs are described in the study manual. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement, the investigator agrees to meet with the CRA during 
study site visits; to ensure that study staff is available to the CRA as needed; to provide the CRA 
access to all study documentation, to the clinical supplies dispensing and storage area; and to 
assist the monitors in their activities, if requested. Further, the investigator agrees to allow the 
sponsor or designee auditors or inspectors from regulatory agencies to review records and to 
assist the inspectors in their duties, if requested.
Data Management 
The sponsor or designee will be responsible for activities associated with the data management 
of this study. The standard procedures for handling and processing records will be followed per 
GCP and the sponsor’s or contract research organization’s (CRO) standard operating procedures. 
A comprehensive data management plan will be developed including a data management plan, 

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database contents, annotated CRF, self-evident correction conventions, query contacts, and 
consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document data review to ensure the accuracy of the corrected 
and/or clarified data. Procedures for soliciting and documenting resolution to data queries are 
described in the Data Management Plan. 
 
Quality Assurance/Audit
This study may be subject to audit by the sponsor or designee. The audits may be undertaken to 
check compliance with GCP guidelines and may include: 
 In-house study file audit 
 Audit of computer database quality control 
 Audit of clinical report quality control 
The sponsor or designee may conduct additional audits on a selection of study sites, requiring 
access to subject notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities according 
to GCP guidelines. The investigator agrees to cooperate with the auditor during the visit and will 
be available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify the sponsor immediately. 
 
Study Termination 
The study may be terminated at the sponsor’s discretion at any time and for any reason. 
 
Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
the sponsor or designee will notify the IRB and regulatory authorities about the regular 
termination of the study as required. 
Premature Study Termination
The study may be terminated prematurely for any reason and at any time by the sponsor, IRB, 
regulatory authorities, or the coordinating investigator. A decision to prematurely terminate the 
study is binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, the sponsor or designee will notify 
the IRB and regulatory authorities as required. The sponsor or designee must clearly explain the 
reasons for premature termination. 
If the study is terminated prematurely, all investigators must inform their subjects and take care 
of appropriate follow-up and further treatment of subjects to ensure protection of the subjects’ 

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interests. Study sites may be asked to have all subjects currently participating in the study 
complete all of the assessments for the Early Termination visit. 
 
Study Site Closure 
At the end of the study, all study sites will be closed. The sponsor may terminate participation of 
a study site at any time. Examples of conditions that may require premature termination of a 
study site include, but are not limited to, the following: 
 Noncompliance with the protocol, with applicable regulations and guidelines, or both. 
 Inadequate subject enrollment.
 
Record Retention 
The investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including, but not limited to, those defined by GCP as essential until at least 
2 years after the notification of submission of the final CSR to regulatory authorities by the 
sponsor. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent 
to destroy all such material. The sponsor shall have 30 days to respond to the investigator’s 
notice, and the sponsor shall have a further opportunity to retain such materials at the sponsor’s 
expense. 
After completing the study, the sponsor will be provided with the original CRFs or at least a 
legible copy and retain the documents at least 5 years after the completion of the study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
subject identification codes, subject files, and other source data until at least 5 years after 
notification of submission of the final CSR to the regulatory authorities by the sponsor. These 
documents need to be retained for a longer period if required by applicable regulatory authorities 
or by agreement with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent 
to destroy all such material. The sponsor shall have 30 days to respond to the investigator’s 
notice, and the sponsor shall have a further opportunity to retain such materials at the sponsor’s 
expense.
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period permitted by the hospital, institution, or private 
practice.
Sample Retention
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed, and the decision has been made 
that none of the samples needs to be reanalyzed or at the completion of the CSR. In addition, 
identifiable samples can be destroyed at any time at the request of the subject.

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Changes to the Protocol
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval by the sponsor. The protocol amendment must be signed by the 
investigator and approved by the IRB before it may be implemented. Protocol amendments will 
be filed with the appropriate regulatory agency. 
Use of Information
All information about the study drug, the sponsor’s operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information supplied by the 
sponsor or designee to the investigator and not previously published, is considered confidential 
and remains the sole property of the sponsor. Case report forms also remain the property of the 
sponsor. The investigator agrees to use this information for purposes of study execution through 
finalization and will not use it for other purposes without the written consent of the sponsor. 
The information developed in this study will be used by the sponsor in connection with the 
continued development of the study drug and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
In order to maintain patient privacy, all CRF, investigational product accountability records, 
study reports and communications will identify the patient by initials and/or the assigned patient 
number. The investigator will grant monitor(s) and auditor(s) from BioXcel (or designee) and 
regulatory authorities access to the patient’s original medical records for verification of data 
gathered on the CRF and to audit the data collection process. The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations 

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15.
FINAL CLINICAL STUDY REPORT
The final CSR will be written according to the “Guideline for Industry (Structure and Content of 
Clinical Study Reports)” from the ICH E3. The final CSR will present a narrative description of 
the clinical, analytical, PK, and statistical results. Tables and figures will be “integrated” into the 
main text, with appendices at the end of the report (e.g., the protocol, sample CRFs, investigator-
related information, test/reference product information, subject data listings). 
The final CSR will be submitted to the appropriate regulatory authorities. 

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16.
ETHICAL AND LEGAL CONSIDERATIONS
16.1.
Declaration of Helsinki and Good Clinical Practice
This study will be conducted in compliance with the November 2016 ICH Guidance for Industry 
E6(R2) GCP and the 1996 Version of the Declaration of Helsinki. 
16.2.
Subject Information and Informed Consent
A properly constituted, valid IRB must review and approve the protocol, the investigator’s 
informed consent document, and related subject information and recruitment materials before the 
start of the study. 
It is the responsibility of the investigator to ensure that informed consent has been obtained from 
the subject or LAR before any activity or procedure is undertaken that is not part of routine care.   
16.3. 
Approval by Institutional Review Board 
A valid IRB must review and approve this protocol before study initiation. Written notification 
of approval is to be submitted by the investigator to the sponsor monitor before shipment of 
investigational drug supplies and will include the date of the committee’s approval and the 
chairperson’s signature. This written approval must consist of a completed sponsor IRB 
Approval Form or written documentation from the IRB containing the same information. 
Until written approval by the IRB has been received by the investigator, no subject may undergo 
any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB. Written approval from 
the IRB, or a designee, must be received by the sponsor before implementation. This written 
approval will consist of a completed IRB Approval form or written documentation from the IRB 
containing the same information. 

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17. 
REFERENCES 
Alderfer BS, Allen MH. Treatment of Agitation in Bipolar Disorder Across the Life Cycle. J 
Clin Psychiatry. 2003; 64 (Suppl 4): 3-9. 
Allen MH, Currier GW, Hughes DH, Docherty JP, Carpenter D, Ross R. Treatment of 
Behavioral Emergencies: A Summary of the Expert Consensus Guidelines. Journal of Psychiatric 
Practice. 2003; 9: 16–38. 
Battaglia J. Pharmacological Management of Acute Agitation. Drugs. 2005; 65 (9): 1207-1222. 
Conn DK, Lieff S. Diagnosing and Managing Delirium in the Elderly. Can Fam Physician. 2001; 
47: 101-108. 
Cummings, J., Mintzer, J., Brodaty, H., Sano, M., Banerjee, S., Devanand, D., Zhong, K. (2015). 
Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus 
clinical and research definition. International Psychogeriatrics, 27(1), 7-17. 
doi:10.1017/S1041610214001963 (https://www.cambridge.org/core/journals/international-
psychogeriatrics/article/agitation-in-cognitive-disorders-international-psychogeriatric-
association-provisional-consensus-clinical-and-research-
definition/38ED46F4469F280437C64405A593A89A]). 
Currier GW, Trenton A. Pharmacological Treatment of Psychotic Agitation. CNS Drugs. 2002; 
16 (4): 219-228. 
Currier GW, Allen MH, Bunney EB, Daniel DG, Francis A, Jagoda A, Zimbroff D. Standard 
Therapies for Acute Agitation. Journal of Emergency Medicine. 2004; Vol. 27: S9–S12. 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. doi: 
10.1016/0022-3956(5)90026-6. PMID: 1202204. 
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of 
dementia. Br J Psychiatry. 1982 Jun;140:566-72. doi: 10.1192/bjp.140.6.566. PMID: 7104545. 
IPA Complete Guides to Behavioral and Psychological Symptoms of Dementia (BPSD) 
|International Psychogeriatric Association (ipa-online.org). 
Jack CR, Bennett DA, Blennow K, et al. 2018 National Institute on Aging-Alzheimer’s 
Association (NIA-AA) Research Framework NIA-AA Research Framework: Toward a 
 of Alzheimer’s disease: Alzheimer’s & Dementia 14 (2018) 535-562. 
https://doi.org/10.1016/j.jalz.2018.02.018  
Kueper JK, Speechley M, Montero-Odasso M. The Alzheimer's Disease Assessment 
Scale-Cognitive Subscale (ADAS-Cog): modifications and responsiveness in pre-dementia 
populations. A narrative review. J Alzheimers Dis. 2018;63(2):423-44. 
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's 
disease: recommendations from the National Institute on Aging-Alzheimer's Association 
workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 
2011;7(3):263-269. doi: 10.1016/j.jalz.2011.03.005. 

BioXcel Therapeutics, Inc. 
Confidential 
BXCL501-303 
Protocol BXCL501-303 Amendment 2 (18Nov2022)
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MHRA. CLH Report: Proposal for Harmonised Classification and Labelling, Substance Name: 
Medetomidine. October 2014. Version 1. 
Montoya, A., A. Valladares, L. Lizan, L. San, R. Escobar and S. Paz (2011). "Validation of the 
Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic 
sample of 278 patients with acute psychosis and agitation in a psychiatric emergency room." 
Health Qual Life Outcomes 9: 18. 
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 
1993 Nov;43(11):2412-4. doi: 10.1212/wnl.43.11.2412-a. PMID: 8232972. 
Ono, H. (2007). "Agitation-Calmness Evaluation Scale (ACES) for evaluation of psychomotor 
excitation and sedation." Jpn. J. Clin. Psychopharmacol.(10): 1063-1066. 
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. 
Osser DN, Sigadel R, Short-Term Inpatient Pharmacotherapy of Schizophrenia. Harvard Review 
of Psychiatry. May-June 2001; Volume 9 (Issue 3): 89-104. 
Rosen J, Burgio L, Kollar M, Cain M, Allison M, Fogleman M, Michael M, Zubenko GS. The 
Patients, The American Journal of Geriatric Psychiatry, Volume 2, Issue 1, 1994, Pages 52-59. 
Schafer et al. 2015 Administration and Scoring Manual Alzheimer’s Disease Assessment Scale – 
Cognitive (ADAS-cog). 10/10/13 (Updated 6/30/15).  Adapted from The Administration and 
Scoring Manual for the Alzheimer’s Disease Assessment Scale 1994 Revised Edition, Richard C. 
Mohs, Ph.D. 
Skinner J, Carvalho JO, Potter GG, et al. The Alzheimer's Disease Assessment 
Scale-Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve 
responsiveness in MCI. Brain Imaging Behav. 2012 Dec;6(4):489-501.