A Phase III Multicenter, Randomized, Double-Blind, Placebo-Controlled Study To Determine Efficacy and Safety of BXCL501 In Agitation Associated With Schizophrenia
Phase: PHASE3
Conditions: Agitation, Schizophrenia, Schizo Affective Disorder, Schizoaffective Disorder, Schizophreniform Disorders
Sponsor: BioXcel Therapeutics Inc

CONFIDENTIAL 
A Phase Ill Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Determine Efficacy and Safety 
of BXCL501 in Agitation Associated with Schizophrenia 
NCT04268303 
01/31/2020 

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2. INVESTIGATOR AGREEMENT 
 
PROTOCOL TITLE:  
A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY TO DETERMINE 
EFFICACY AND SAFETY OF BXCL501 IN AGITATION 
ASSOCIATED WITH SCHIZOPHRENIA  
 
 
PROTOCOL NUMBER:  
BXCL501-301 
 
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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Table 3.1:  
Schedule of Events 
 
 
Treatment Evaluation Day 1 
 
Activity 
Screening 
Pre-
Dose1 
 
Post Dose Time1 
Day 2 
Follow-Up 
(+1) 
Day 3 
Discharge 
Day 7 
(+2) 
Time point 
Pre-
treatment 
-1 hr to 
time 0 
10 
min 
20 
min 
30 
min 
45 
min 
1  
hr 
1.5 
hr 
2 
hr 
4 
hr 
6 
hr 
8 
hr 
24 hr 
(-9/+12 hr) 
 
End of 
Study 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breathalyzer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Safety Labs2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
ECG with rhythm strip 3  
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Pulse oximetry 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
Resting vital signs4 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Orthostatic vital signs4 
X 
X 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
Admit to Unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administration 10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PANSS9 
 
X 
 
 
 
 
 
 
 
 
X  
 
X 
 
 
PCRS5 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
PEC5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ACES5 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
CGI-Severity6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-Improvement6 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 

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4. TABLE OF CONTENTS 
 
1. 
PROCEDURES IN CASE OF EMERGENCY ............................................................3 
2. 
INVESTIGATOR AGREEMENT ...............................................................................4 
3. 
SYNOPSIS ...................................................................................................................5 
4. 
TABLE OF CONTENTS ...........................................................................................13 
4.1 
List of Tables .....................................................................................................16 
5. 
LIST OF ABBREVIATIONS AND DEFINTIONS OF TERMS ..............................17 
6. 
INTRODUCTION ......................................................................................................20 
6.1 
Background and Rationale ................................................................................20 
6.2 
Description ........................................................................................................22 
7. 
OBJECTIVES .............................................................................................................23 
7.1 
Primary Endpoint: .............................................................................................23 
7.2 
Key Secondary Endpoint: ..................................................................................23 
8. 
STUDY DESIGN .......................................................................................................24 
8.1 
Overall Study Design and Plan .........................................................................24 
8.2 
Discussion of Study Design ..............................................................................24 
8.3 
Study Sites .........................................................................................................25 
9. 
SUBJECT POPULATION .........................................................................................26 
9.1 
Selection of Study Population ...........................................................................26 
9.2 
Inclusion Criteria ...............................................................................................26 
9.3 
Exclusion Criteria ..............................................................................................26 
9.4 
Removal of Subjects from Therapy or Assessment ..........................................27 
10.  STUDY TREATMENTS ............................................................................................28 
10.1  Method of Assigning Subjects to Treatment Groups ........................................28 
10.2  Identification of Investigational Product ...........................................................28 
10.3  Treatment Administration .................................................................................28 
10.4  Storage ...............................................................................................................28 
10.5  Labeling .............................................................................................................28 
10.6  Drug Accountability ..........................................................................................29 
10.7  Blinding and Unblinding Treatment Assignment .............................................29 
10.8  Treatment Compliance ......................................................................................29 
10.9  Concomitant Medications ..................................................................................29 
Permitted Therapies ..........................................................................................29 
Prohibited Therapies .........................................................................................30 
11.  STUDY PROCEDURES ............................................................................................31 

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11.1  Screening ...........................................................................................................31 
11.2  Day 1, Pre-Dose ................................................................................................31 
11.3  Day 1, Post-Dose Assessments .........................................................................32 
11.4  Day 2 (+1), Follow Up ......................................................................................33 
11.5  Day 3, Discharge ...............................................................................................33 
11.6  Day 7+2 .............................................................................................................34 
12.  STUDY ASSESSMENTS ..........................................................................................35 
12.1  Efficacy .............................................................................................................35 
PANSS – Excitatory Component (PEC) ...........................................................35 
Agitation-Calmness Evaluation Scale (ACES) .................................................35 
CGI-S and CGI-I ...............................................................................................35 
Likert scales ......................................................................................................36 
12.2  Pharmacokinetics ...............................................................................................37 
Sample Collection & Processing .......................................................................37 
Sample Storage .................................................................................................37 
Sample Shipment ..............................................................................................37 
Analytical Procedures .......................................................................................38 
12.2.1.1  Bioanalytical Sample Analyses .................................................38 
12.2.1.2  Bioanalytical Methodology .......................................................38 
12.3  Safety .................................................................................................................38 
Adverse Events .................................................................................................39 
12.3.1.1  Adverse Event Definitions ........................................................39 
12.3.1.2  Eliciting and Documenting Adverse Events .............................40 
12.3.1.3  Reporting Adverse Events.........................................................40 
12.3.1.4  Follow-up of Adverse Events....................................................42 
C-SSRS .............................................................................................................42 
Laboratory Safety Assessments ........................................................................42 
Vital Signs .........................................................................................................43 
Electrocardiogram .............................................................................................44 
Physical Examination ........................................................................................44 
Concomitant Medications .................................................................................44 
Likert scale ........................................................................................................44 
13.  STATISTICAL METHODS .......................................................................................46 
13.1  General Considerations .....................................................................................46 
13.2  Analysis Populations .........................................................................................46 
13.3  Statistical Analyses ............................................................................................46 
Subject Disposition and Demographic Characteristics .....................................46 

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Efficacy Analyses .............................................................................................46 
Safety Analyses .................................................................................................48 
Pharmacokinetic Analyses ................................................................................48 
13.4  Sample Size Determination ...............................................................................49 
14.  STUDY CONDUCT ...................................................................................................51 
14.1  Sponsor and Investigator Responsibilities ........................................................51 
Sponsor Responsibilities ...................................................................................51 
Investigator Responsibilities .............................................................................51 
14.2  Site Initiation .....................................................................................................51 
14.3  Study Documents ..............................................................................................52 
Good Clinical Practice Documents ...................................................................52 
Case Report Forms ............................................................................................52 
Source Documents ............................................................................................53 
14.4  Data Quality Control .........................................................................................53 
Monitoring Procedures ......................................................................................53 
Data Management .............................................................................................53 
Quality Assurance/Audit ...................................................................................54 
14.5  Study Termination .............................................................................................54 
Regular Study Termination ...............................................................................54 
Premature Study Termination ...........................................................................54 
14.6  Study Site Closure .............................................................................................55 
Record Retention ...............................................................................................55 
Sample Retention ..............................................................................................56 
14.7  Changes to the Protocol .....................................................................................56 
14.8  Use of Information ............................................................................................56 
15.  FINAL CLINICAL STUDY REPORT ......................................................................57 
16.  ETHICAL AND LEGAL CONSIDERATIONS ........................................................58 
16.1  Declaration of Helsinki and Good Clinical Practice .........................................58 
16.2  Subject Information and Informed Consent ......................................................58 
16.3  Approval by Institutional Review Board ...........................................................58 
17.  REFERENCES ...........................................................................................................59 
 
 

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4.1 
List of Tables 
Table 1.1:  
Sponsor/CRO Contact Information .........................................................3 
Table 3.1:  
Schedule of Events ................................................................................10 
Table 13.1: 
Estimated Sample Size group for power of 0.90 ...................................49 
Table 13.2: 
Estimated Sample Size group for power of 0.85 ...................................49 
  
 

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5. LIST OF ABBREVIATIONS AND DEFINTIONS OF TERMS 
Abbreviation 
Definition 
ACES 
Agitation-Calmness Evaluation Scale 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
API 
Active Pharmaceutical Ingredient 
AUC 
Area under the plasma concentration vs time curve 
BP 
Blood pressure 
BMI 
Body Mass Index 
C 
Celsius/Centigrade 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic blood pressure 
Dex or DEX 
Dexmedetomidine 
DLT 
Dose Limiting Toxicity 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic acid 
ET 
Early Termination 
FDA 
US Food and Drug Administration 
FD&C 
United States Federal Food, Drug, and Cosmetic Act 
g 
gram 
GABA 
Gamma-Amino Butyric Acid 

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Abbreviation 
Definition 
GCP 
Good Clinical Practices 
HCl 
Hydrochloride 
HR 
Heart rate 
hr 
hour 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IM 
Intramuscular 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
IUD 
Intrauterine Device 
IV  
Intravenous 
kg 
kilogram 
LC/MS/MS 
Liquid chromatography-tandem mass spectrometry 
LD 
Listed Drug 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MHRA 
Medicines and Healthcare products Regulatory Agency 
Min 
Minutes 
mL 
milliliter 
mm 
millimeters 
mmHG 
millimeters of mercury 
MMRM 
Mixed model repeated measures 
MS 
Mass spectrometry 
MTD 
Maximum tolerated dose 
MW 
Molecular weight 
PANSS/PANSS-EC 
Positive and Negative Syndrome Scale/ Positive and Negative 
Syndrome Scale – Excited Component 
PCRS 
Placebo-Control Reminder Script 
PD 
Pharmacodynamics 

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Abbreviation 
Definition 
PEC 
Positive and Negative Syndrome Scale – Excited Component 
pg 
picogram 
pH 
measure of hydrogen ion concentration 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
po 
oral/by mouth 
POC 
Proof of Concept 
PP 
Per Protocol 
RASS 
Ramsay Sedation Scale 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SL 
Sublingual  
THC 
Tetrahydrocannabinol 
Tmax 
Time that drug is present at the maximum concentration in serum 
µg/µcg 
Microgram 
UDS 
Urine Drug Screen 
USP 
United States Pharmacopeia  

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6. INTRODUCTION 
6.1 
Background and Rationale 
Background 
Agitation is a severe, disruptive, and morbid complication of many chronic mental illnesses, 
including schizophrenia (Osser and Sigadel 2001), dementia (Conn and Lieff 2001), and bipolar 
disorder (Alderfer and Allen 2003). Currently, the standard of care in the treatment of acute 
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 
onset of action after both oral and intramuscular administration is typically 30-60 min due to 
slow absorption into the systemic circulation. Slow onset of action extends suffering of agitated 
patients and increases the need for physical restraint or seclusion (Allen et al. 2003).  
In contrast to oral or IM administration, intravenous injection (IV) results in onset of anti-
agitation action within 1-5 min (Allen et al. 2001, 2003). However, it is generally impractical to 
use IV administration in agitated patients. According to expert consensus guidelines developed 
by 50 leading US experts in behavioral emergencies (Allen et al. 2001), speed of onset of anti-
agitation effects was viewed as the most important factor in selecting an agitation treatment. The 
discrepancy between the need for speed of onset in treatment of agitation and the slow onset of 
most frequently utilized treatments represents a substantial unmet medical need in the population 
of patients with behavioral emergencies. An alternative non-invasive yet rapidly delivered 
medication which produces a rapid calming effect that allows patients to participate in their care 
and treatment would find use in the pharmacological management of acute agitation.  
BioXcel Therapeutics Inc. is developing a sublingual film formulation of dexmedetomidine 
(BXCL501) for the acute treatment of hyper-arousal in agitated patients with schizophrenia, 
bipolar disorder, and dementia. Dexmedetomidine is a highly selective α2 adrenoceptor agonist 
on presynaptic neurons. The stimulation of these receptors in the locus coeruleus leads to a 
decrease in norepinephrine release from presynaptic neurons with inhibition of postsynaptic 
activation, which attenuates central nervous system (CNS) arousal, and diminishes the fight-or-
flight response (MHRA 2014). By controlling norepinephrine release from the locus coeruleus, 
BXCL501 has a novel mode of action compared to current therapies (D2 antagonists and GABA 
agonists) and is previously untested for the treatment of acute agitation. In addition, because it 
enters the blood stream directly by the sublingual route and bypasses first-pass metabolism in the 
liver, dexmedetomidine from BXCL501 is less susceptible to variations in hepatic function than 
orally administered drugs. 
Dexmedetomidine is currently approved in the United States (US) as the intravenous injectable 
formulation, Precedex® (Precedex US Package Insert, 2016), for acute procedural and ICU 
sedation. Dexmedetomidine has been administered by the oral, nasal, and oral mucosal routes in 
both nonclinical and clinical studies with substantial bioavailability via the oral mucosal route 
and no route-specific safety signals (oral mucosal or gastrointestinal).  
BXCL501 is a sublingual thin film formulation of dexmedetomidine which is intended for the 
acute treatment of agitation. BXCL501 is designed as a self-administered discrete low dose film 
with mucoadhesive properties. It is therefore expected that its administration in agitated patients 

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will lead to faster onset of clinical response than administration of oral or intramuscular 
preparations.  
BXCL501 was evaluated for PK, bioavailability and safety in a randomized, double-blind, 
placebo-controlled trial. Doses from 10 to 40µg (Study BXCL501-101) in healthy volunteers 
produced lower systemic exposure (Cmax and AUCs) compared to the PK parameters presented 
in the Precedex package insert and was safe and well tolerated. Sedation as measured by visual 
analog scale and other measures were similar for BXCL501 in contrast with placebo at each dose 
level; while there was a greater incidence of arousable sedation for the highest dose tested. 
Cardiovascular activity was monitored with relatively few incidents of bradycardia, hypotension 
or orthostatic hypotension that were either non-reproducible or generally mild and transient.  
A multicenter, double-blind, placebo-controlled, Phase 1b trial (Study BXCL501) was conducted 
in agitated subjects with schizophrenia to evaluate the safety and efficacy BXCL501. Subject 
self-administration of BXCL501, with doses ranging from 20 to 180µg, was associated with a 
safe, well-tolerated and effective calming as measured by a reduction in PEC scores at 2 hours. 
Preliminary results of the BXCL501-102 study suggested calming effects as measured by group 
mean reduction from baseline PEC score achieving statistically significant separation from 
placebo as early as 45 min, at 2 hr and maintained through 6 hrs and longer. There were no SAEs 
and treatment-emergent AEs were generally transient, mild to moderate in severity. The most 
commonly reported AEs were arousable, intermittent somnolence (of mild to moderate severity) 
and dry mouth. There were no clinically meaningful changes in cardiovascular parameters in the 
180µg dose group and no medical interventions were necessary.  
Agitation can be seen in patients with schizophrenia. While the etiology of agitation is not fully 
understood, hypothesized dysfunctions in norepinephrine, dopamine, serotonin and GABA 
systems are consistent with the demonstrated efficacy of agents such as benzodiazepines and 
typical and atypical antipsychotics (Lindenmayer, 2000; Battaglia 2005; Berk 2005). In recent 
years, formulations of the atypical antipsychotics Zyprexa (Meehan, 2001), Geodon (Bellnier, 
2002), and Abilify (Sanford, 2008) for intramuscular injection have received FDA approval for 
treating agitation in patients with bipolar I disorder with mania or mixed episodes (with or 
without psychotic features), as well as approval for treating agitation in patients with 
schizophrenia. The schizophrenia and bipolar disorder studies have generally utilized similar 
clinical trial designs to evaluate the efficacy and safety of these agents over a 24 hour period 
following intramuscular injection. Furthermore, for each agent, similar efficacious dose ranges 
were approved for treating agitation in bipolar disorder and schizophrenia. 
Study Rationale 
The purpose of the present Phase 3 study is to assess the safety and efficacy of BXCL501 in the 
treatment of acute agitation in patients with schizophrenia, schizoaffective disorder or 
schizophreniform disorder and to assess the safety and tolerability over a 24-hour period. The 
study will be conducted in patients who are either newly admitted to a hospital setting or a 
research unit for acute agitation, or already in-hospital for the treatment of schizophrenia. 
Patients meeting entry criteria will be randomized to BXCL501 at a dose of 120µg or 180µg, or 
to matching placebo. Following administration of study drug, assessment of agitation will be 
conducted at serial time points using standard agitation scales over a 24-hour period. The 
PANSS Excited Component (PEC) scale will be the primary efficacy measure. 
 

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8. STUDY DESIGN 
8.1 
Overall Study Design and Plan 
The study will enroll approximately 375 subjects randomized 1:1:1 to dose regimens of 180µg, 
120µg BXCL501, or placebo stratified by age < 65 and age ≥ 65. The doses were selected based 
on the results of the prior Phase Ib clinical trial (Study BXCL501-102).  
Male and female adults with acute agitation associated with schizophrenia, schizoaffective 
disorder, or schizophreniform disorder will be enrolled.  
Eligible subjects (acutely agitated subjects with schizophrenia, schizoaffective, or 
schizophreniform disorder) may be identified in outpatient clinics, mental health, psychiatric or 
medical emergency services including medical/psychiatric observation units, or as newly 
admitted to a hospital setting for acute agitation or already in hospital for chronic underlying 
conditions. Subjects will be domiciled in a clinical research setting or hospitalized to remain 
under medical supervision while undergoing screening procedures to assess eligibility. 
Upon confirmation of eligibility, subjects will be randomized to 180µg BXCL501 or 120µg 
BXCL501 or matching placebo.  Efficacy and safety assessments will be conducted periodically 
before and after dosing.  
Vital Signs, pulse oximetry,  and ECG with rhythm strip will be measured as per schedule of 
assessments, prior to any PK assessments. Participants will be allowed water as desired 15 
minutes after completion of dosing. Safety and tolerability assessments will be conducted at 
various timepoints. Please refer to the Table 3.1 Schedule of events for details. 
Any abnormal vital sign measurement, clinical laboratory test, physical examination finding, or 
ECG parameter deemed clinically significant by the investigator will be repeated, including test 
results obtained on the final study day or upon early termination. For any test abnormality 
deemed clinically significant, repeat analysis will be performed during the follow-up period and 
until the value returns to baseline (or within normal limits) or the investigator deems the 
abnormality to be stable and no longer of clinical concern.    
Approximately 4 mL of venous blood (to obtain a minimum of 1.2 mL plasma) will be taken into 
K2-EDTA tubes at set time intervals for the determination of plasma concentrations of study 
drug (or Placebo). The PK plasma samples should be collected within 10 min of the scheduled 
sampling time on Day 1. Blood samples will be collected per Table 3-1 Schedule of Events.  
8.2 
Discussion of Study Design 
This is a definitive study to support the safety and efficacy evaluation of BXCL501 for the acute 
treatment of agitation in schizophrenia.  The BXCL501-301 study is designed to characterize the 
efficacy, safety and tolerability of BXCL501 (sublingual film formulation of DEX, HCl) in 
agitation associated with schizophrenia, schizoaffective disorder or schizophreniform disorder. A 
dose of BXCL501 was chosen based on results from BXCL501-102 that showed rapid efficacy 
in a large proportion of subjects, was well tolerated and had an acceptable safety profile. In the 
event of persistent or recurrent agitation, investigators may choose to repeat dose at 90µg or 
60µg (half of 180µg or 120µg film) after the 2-hour time point as measured by a PEC change 
from baseline <40% but in the absence of safety concerns. Patients can only be re-dosed if they 
are hemodynamically stable, not hypotensive (must be greater than 90/60 systolic/diastolic) and 

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not bradycardic (must be greater than 60 bpm). Patients also cannot be re-dosed if they are  
orthostatic (a drop of > 20 mm Hg systolic, or 10 mm Hg diastolic) or if they are experiencing an 
AE that when assessed by the PI precludes redosing. The maximum number of repeat doses per 
subject is 2, during the 12 hours post first dose. Doses may not be administered sooner than 2 
hours after a previous dose. If the PEC change from baseline is >40% repeat dosing is not 
allowed. 
Placebo was chosen as a comparator to more accurately assess efficacy as well as safety and 
tolerability.  The randomized, double blind parallel-group design ensures the sponsor, all 
subjects, and study staff involved are shielded from treatment assignment and outcomes and 
therefore will minimize any potential bias. The randomization ratio provides an additional 
element to ensure blinding by decreasing the odds of guessing treatment arms.        
8.3 
Study Sites 
The study will take place at up to 30 sites in the US. 

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9. SUBJECT POPULATION 
9.1 
Selection of Study Population 
9.2 
Inclusion Criteria 
A subject will be eligible for inclusion in the study if he or she meets the following criteria: 
1. Male and female patients between the ages of 18 to 75 years, inclusive. 
2. Patients who have met DSM-5 criteria for schizophrenia, schizoaffective, or 
schizophreniform disorder. 
3. Patients who are judged to be clinically agitated at Screening and Baseline with a total 
score of ≥ 14 on the 5 items (poor impulse control, tension, hostility, uncooperativeness, 
and excitement) comprising the PANSS Excited Component (PEC). 
4. Patients who have a score of ≥ 4 on at least 1 of the 5 items on the PEC at Baseline. 
5. Patients who read, understand, and provide written informed consent. 
6. Patients who are in good general health prior to study participation as determined by a 
detailed medical history, physical examination, 12-lead ECG with rhythm strip, blood 
chemistry profile, hematology, urinalysis, and in the opinion of the Principal Investigator. 
7. 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 alone. 
9.3 
Exclusion Criteria 
A subject will be excluded from the study if he or she meets the following criteria: 
1. Patients with agitation caused by acute intoxication, including positive identification of 
alcohol by breathalyzer or drugs of abuse (with the exception of THC) during urine 
screening.  
2. Use of benzodiazepines, other hypnotics or antipsychotic drugs in the 4 hours before 
study treatment.  
3. Treatment with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, 
alfuzosin, or prazosin) or other prohibited medications. 
4. Patients judged to be at serious risk of suicide must be excluded.  
5. Female patients who have a positive pregnancy test at screening or are breastfeeding. 

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10. STUDY TREATMENTS 
10.1 Method of Assigning Subjects to Treatment Groups 
Upon confirmation of eligibility, subjects will be randomized to 180µg BXCL501 or 120µg 
BXCL501 or placebo.  
Randomization will be 1:1:1 (180µg BXCL501: 120µg BXCL501:Placebo and stratified by age 
< 65, age ≥ 65) with 125 patients assigned to each arm by a permuted block design. Study 
randomization will be computer generated. 
10.2 Identification of Investigational Product 
BXCL501 will be provided as a small, solid-dose film formulation, approximately 193.6 mm2 in 
area and 0.7 mm thick, designed to completely dissolve in the SL space within 1-3 min.  
BXCL501 Sublingual Film 180µg, 120µg and placebo will be packaged as individual films in a 
heat-sealed white foil pouch with a drug product label. The pouch has a white colored outer layer 
with foil colored inner layer. Individual film appearance is as follows:  
 180µg – Green rectangular thin film (~22 mm x 8.8 mm) 
 120µg – Green rectangular thin film (~22 mm x 8.8 mm) 
 Placebo – Green rectangular thin film (~22 mm x 8.8 mm) 
BioXcel Therapeutics, Inc. will provide an adequate supply of study drug to the sites. 
10.3 Treatment Administration 
 
At the time of dosing, patients will be instructed on how to take the investigational product 
sublingually, and that they should retain the investigational product in the sublingual cavity until 
dissolved.  The patient will self-administer under the supervision of a trained staff member. If the 
patient is unable to self-administer, the event will be recorded, and the subject's participation will 
conclude.  
 
In the event of persistent or recurrent agitation, investigators may choose to re- dose at 90µg or 
60µg (cutting half of the 180µg or 120µg film) after the 2-hour time point as measured by a PEC 
change from baseline ≤40% but in the absence of safety concerns. 
10.4 Storage 
No special transport or storage conditions are required for BXCL501. Packaged films can be 
stored at room temperature (25°C) and ambient humidity. 
10.5 Labeling 
Each pouch of study drug will be labeled with study-specific information that meets all 
applicable regulatory requirements. 

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11. STUDY PROCEDURES 
Subjects will provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
The schedule of events to be performed during the study is provided in Table 3.1. 
11.1 Screening  
Subjects must be screened and randomized into the study before dosing. When possible, 
screening and randomization will take place on the same day.  
The following procedures will be performed at Screening (refer to the Schedule of Events table): 
 Obtain written informed consent 
 Review inclusion and exclusion criteria 
 Collect demographic information 
 Record medical history, including prior and current therapies (e.g. prescription and non-
prescription medications) 
 Physical examination including weight, height, body mass index, and vital signs  
 Urine pregnancy test for all females of childbearing potential 
 12-lead ECG with rhythm strip 
 Collect blood and urine samples for clinical laboratory tests (hematology, clinical 
chemistry, urinalysis, and urine drug screen) 
 Alcohol breathalyzer 
 MINI 
 Placebo-Control Reminder Script (PCRS) (prior to PEC) 
 PEC 
 CGI-S 
 C-SSRS 
 Adverse events are recorded following informed consent 
 Record concomitant medication use 
 Admit to Clinical Research Unit (for subjects not currently admitted) 
The Screening Visit may be conducted over more than one day; however, all procedures must be 
completed prior to subject randomization and within 28 days of signing informed consent. 
Screen Failures: Subjects who fail inclusion and/or exclusion criteria may be rescreened for the 
study.  Subjects may only be rescreened one time.  
11.2 Day 1, Pre-Dose 
The following procedures will be performed prior to dosing: 

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 Review inclusion and exclusion criteria 
 Assess and record AEs  
 Record concomitant medication use 
 Resting (recumbent) and Orthostatic Vital signs 
 Pulse Oximetry 
 C-SSRS 
 ECG with rhythm strip (not required if screening ECG is conducted on the day of dosing) 
 PANSS 
 CGI-S 
 Randomization 
 Placebo-Control Reminder Script (PCRS) (prior to PEC) 
 PEC (within 15 min of dosing) 
 ACES (within 15 min of dosing) 
Upon completion of the pre-randomization procedures, the subject will be randomized to study 
treatment (180µg BXCL501 or 120µg BXCL501 or placebo), study drug administration will 
occur, and the following procedures will be performed (Refer to the Schedule of Events for 
specific time points): 
11.3 Day 1, Post-Dose Assessments 
 CGI-I  
 PCRS (prior to PEC) 
 PEC (prior to PANSS)  
 ACES  
 PANSS 
 Vital Signs (Resting/Recumbent and Orthostatic) 
 ECG with rhythm strip 
 Pulse oximetry 
 Buccal (SL) Assessment 
 Likert scales 
 Likability Questions 
 Assess and record AEs  
 Record concomitant medication use 

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 Plasma sample for PK analysis. A sample may not be collected if the physician in charge 
of the patient indicates in the source documents that the patient is in a mental state that is 
not conducive to PK sample collection. 
 
Investigators may choose to repeat dosing with the 90µg or 60µg dose (half of 180µg or 120µg 
film) after the 2-hour time point for persistent or recurrent agitation (PEC change from baseline 
<40%) but only in the absence of safety concerns. Patients can only be re-dosed if they are 
hemodynamically stable, not hypotensive (must be greater than 90/60 systolic/diastolic) and not 
bradycardic (must be greater than 60 bpm). Patients also cannot be re-dosed if they are  
orthostatic (a drop of > 20 mm Hg systolic, or 10 mm Hg diastolic) or if they are experiencing an AE 
that when assessed by the PI precludes redosing. All 2 hour assessments (including efficacy and 
safety) must be completed before repeat dosing may occur. The maximum number of repeat 
doses allowed per subject is 2, during the 12 hours post first dose.  Doses may not be 
administered sooner than 2 hours after a previous dose. If the PEC change from baseline is >40% 
repeat dosing is not allowed. As noted in the Schedule of Events (Table 3.1), all assessments 
listed at the 2-hour post first dose timepoint should be repeated at 2 hours post every re-dose. 
11.4 Day 2 (+1), Follow Up 
The following procedures will be performed on Day 2: 
 ECG with rhythm strip 
 Physical exam including weight 
 Resting/Recumbent and Orthostatic Vital sign and weight measurements   
 PCRS (prior to PEC) 
 PEC (prior to PANSS) 
 PANSS 
 C-SSRS 
 Buccal (SL) Assessment  
 Record concomitant medication use 
 Assess and record AEs 
11.5 Day 3, Discharge 
The following procedures will be performed on Day 3, Discharge: 
 Collect blood and urine samples for clinical laboratory tests (hematology, clinical 
chemistry, and urinalysis) 
 Resting/Recumbent and Orthostatic Vital signs 
 C-SSRS 
 Record concomitant medication use 
 Assess and record AEs 

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The protocol permits a maximum 3 overnight stays from allowed admission to the Clinical 
Research Unit to Discharge. If more nights are required, Medical Monitor approval is required. 
11.6 Day 7+2 
The following procedures will be performed on Day 7+2: 
 Collect blood and urine samples for clinical laboratory tests (hematology, clinical chemistry, 
and urinalysis) 
 Resting/Recumbent and Orthostatic Vital signs 
 Record concomitant medication use 
 Assess and record AEs 

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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. 
PANSS – Excitatory Component (PEC) 
Assessment of drug effect on acute agitation will be done using the Positive and Negative 
Syndrome Scale – Excited Component (PEC). The PEC comprises 5 items associated with 
agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement; each 
scored 1 (minimum) to 7 (maximum). The PEC, the sum of these 5 subscales, thus ranges from 5 
to 35. 
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.  
CGI-S and CGI-I 
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 illness will be assessed based on following scale: 
0 = Not assessed 
1 = Not at all ill 
2 = Borderline mentally ill 
3 = Mildly ill 
4 = Moderately ill 
5 = Markedly ill 
6 = Severely ill 
7 = Among the most extremely ill subjects 
Drug response on agitation will be evaluated by the Clinical Global Impressions – Improvement 
(CGI-I).  It will be performed at 30 minutes, 1, 2 and 4 hrs post dose. The CGI-I scores range 
from 1 to 7: 
0=not assessed (missing), 
1=very much improved, 
2=much improved, 
3=minimally improved, 
4=no change, 

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5=minimally worse, 
6=much worse, 
7=very much worse 
Both CGI-I and CGI-S will be focused on the severity of agitation rather than the severity of the 
overall illness of schizophrenia. 
Placebo-Control Reminder Script (PCRS) 
The Placebo-Control Reminder Script (PCRS) © Hassman and Cohen, 2019, Version 5.0 educates clinical trial 
participants of key causes of the placebo and nocebo effects, namely the tempering of participant 
study expectations, reminding subjects what a placebo is and how that relates to their reporting 
of symptoms and potential side effects, and explaining how interactions with research site staff 
differ from their experience with previous providers. To do this, the PCRS informs subjects that 
they are to be honest about their symptoms, site staff have no expectations of symptom 
improvement or worsening and will not be disappointed if they feel better, worse or the same, 
and asks participants to explain in their own words its content to ensure comprehension. The 
PEC Rater will read the PCRS study source before administering the PEC to EACH subject at 
EACH Visit (time point) listed on the study specific PCRS, typically taking about 2 minutes to 
read. 
 
The Positive and Negative Syndrome Scale (Structured Clinical Interview PANSS)  
The (SCI PANSS) is a tool that measures the severity of schizophrenia symptoms. It contains 
four basic domains: Positive, Negative, general Psychopathology, and a Composite scale. The 
composite scale is derived by subtracting the Negative Scale score from the Positive Scale score 
and can indicate the ratio of positive to negative symptoms.   The SCI_PANSS contains yes-no 
questions as well as open-ended questions. Each of the thirty items of the SCI-PANSS can be 
scored or rated. The seven rating points represent increasing levels of severity. The rating points 
are labeled as:   1 – Absent   2 – Minimal   3 – Mild   4 – Moderate   5 – Moderate Severe   6 – 
Severe   7 – Extreme.  
Likert scales 
After dosing with the study drug, subjects will assess their preference of the study medication by 
answering the statements "I like the taste of the medication” and “The medication is 
acceptable”— using a five-level Likert scale, as below:  
 Strongly disagree 
 Disagree 
 Neither agree nor disagree 
 Agree 
 Strongly agree 
 
Drug likability 
Subjects will also 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.  

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12.2 Pharmacokinetics 
Blood samples (4 ml) will be collected per Table 3-1 Schedule of Events. A sample may not be 
collected if the physician indicates in the source documents that the patient is in a mental state 
that is not conducive to PK sample collection.  
For each subject, up to 3 blood samples (12 mL of blood) will be collected during the study for 
PK analysis. In addition, approximately 30 mL of blood will be collected at screening, 
approximately 15 mL of blood will be collected at Day 3 Discharge, and approximately 15 mL 
of blood will be collected at Day 7(+2) for clinical laboratory testing. The total volume of blood 
collected during the study is expected to be approximately 72 mL. Whenever possible for all 
SAEs a blood sample for PK analysis will be drawn to evaluate a potential relationship with 
exposure.  
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 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 eight (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. Centrifuge blood 
samples at approximately 1500g 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. 
 The time elapsed from collection of the blood sample to completion of centrifugation 
should be no more than 60 minutes. 
Sample Storage 
Plasma samples will be placed in a storage freezer at -70°C (± 12°C) or on dry ice within 120 
minutes of the blood collection. Samples should be placed in a - 60°C to - 80°C freezer until 
shipment.  20°C freezers can also be used for a short period of time (maximum one month) until 
they are shipped to the bioanalytical laboratory. 
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. 

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will notify the sponsor. Should this occur, sponsor will notify FDA, and sponsor may choose to 
continue dosing the patients at a lower dose.  
Adverse Events 
12.3.1.1 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. 
Preexisting 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. 
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 

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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. 
12.3.1.2 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.  Adverse events will be collected from the time of consent 
through the Day 7 (End of Study) or Early Discontinuation visit. 
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 from any data collected on the AE 
page of the CRF (e.g., clinical laboratory values, physical examination findings, and ECG 
changes) or other documents that are relevant to subject safety. 
12.3.1.3 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.  The latest version of the Med DRA 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 12.3.1.1) to the medical monitor within 24 hours of first becoming aware of the event 
by telephone.  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 

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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. 
12.3.1.3.3 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. 
12.3.1.4 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. 
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 Baseline/Screening version will be conducted at 
Screening. The C-SSRS Since Last Visit version will be conducted 24 hours post dosing. 
Laboratory Safety Assessments  
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Events (Table 3.1). 

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At indicated timepoints orthostatic measurement of systolic, diastolic blood pressure, and heart 
rate will be measured after the subject has been standing for a total of 1, 3 and 5 minutes at the 
time points specified in the schedule of events (Table 3.1).  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.  
If the first measurement of vital signs (SBP, DBP, and pulse) shows the following, vital signs 
will be measured again in triplicate (same arm, separated by at least 1 minute) for; 
Systolic Blood Pressure <90 mmHg 
Diastolic Blood Pressure <60 mmHg 
Pulse < 60 bpm 
 Electrocardiogram 
A 12-lead ECG with rhythm strip will be performed at Screening, Pre-dose, 2, and 24 hours post 
dose and 2 hours post any re-dose. Date and time of ECG, ventricular heart rate (beats/minute), 
P-R Interval, QRS Duration, QT Interval (msec) will be collected. QTcF (msec) will be 
calculated. 
 
Pulse Oximetry 
Pulse oximetry will be performed at pre-dose and repeated 30 mins,1, 2, 4, and 8 hours post 
dose. (Table 3.1) 
 Physical Examination 
A standard physical examination will be performed at Screening and 24 hours post dose.  The 
examination will include assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, 
heart, cardiovascular, abdomen, lymph nodes, and musculoskeletal system/extremities.  Interim 
physical examinations will be performed at the investigator’s discretion if necessary, to evaluate 
AEs or clinical laboratory abnormalities. 
Height and weight will be measured at Screening and weight will be measured again at the Day 
of discharge.  BMI will be calculated and recorded. 
 Concomitant Medications 
Concomitant medications will be reviewed and documented each day during the study. 
Likert scale  
After dosing with the study drug, subjects will assess their preference of the study medication by 
answering the statements "I like the taste of the medication” and “The medication is 
acceptable”— using a five-level Likert scale as below:  
 Strongly disagree 
 Disagree 
 Neither agree nor disagree 
 Agree 

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 Strongly agree 
Drug likability 
Subjects will also 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.  

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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. 
13.2 Analysis Populations 
The following analysis populations are planned:  
 Safety Population: All subjects who receive study drug. 
 Intent to treat (ITT) Population: All subjects in the Safety Population who have a PEC 
Score post-dose; 
 Per Protocol (PP) Population: All subjects in the ITT Population with no major protocol 
deviations; 
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 medication. Missing data will be imputed using multiple imputation. As the 
prior studies had little missing data, it is anticipated that methods for monotone missing data will 
be used with values imputed as needed. Efficacy analyses and summaries will be presented for 
both the ITT Population and the PP Population, with the former being primary. Details of the 
statistical analyses will be provided in the Statistical Analysis Plan which will be finalized prior 
to database lock. 
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 (BMI), will be summarized by treatment for the Safety Population. 
Efficacy Analyses 
The primary efficacy endpoint of the study will be the absolute change from baseline in the PEC 
total score at 120 min. The intent to treat population will be analyzed and consist of all patients 
who take any study medication and who had both baseline and at least 1 efficacy assessment 
after dosing. Observations recorded after use of rescue medication will be censored (considered 
missing). The null and alternative hypotheses to be tested are stated as H01: ∆BXCL501_180 = ∆PBO and 
HA1: ∆BXCL501_180 ≠ ∆PBO and H02: ∆BXCL501_120 = ∆PBO and HA2: ∆BXCL501_120 ≠ ∆PBO, where ∆BXCL501_180 
denotes the change from baseline in the PEC at 2 hours post-dose in the BXCL501 180 µg 
group, ∆BXCL501_180 denotes the change from baseline in the PEC at 2 hours post-dose in the 
BXCL501 180 µg group, ∆BXCL501_120 denotes the change from baseline in the PEC at 2 hours 

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The exploratory outcomes will be analyzed using a variety of techniques depending on the 
outcome and including two-sample t-tests, Fisher’s exact test, Kaplan-Meier curves for time-to-
event outcomes and descriptive methods such as box plots, frequency distributions and shift 
tables. All significance levels will be reported as nominal levels. 
Safety Analyses 
All safety analyses will be performed using the Safety Population. All subjects who received at 
least one dose of study drug will be included in the population for safety analysis. 
Adverse events (AEs) will be characterized by type, severity, seriousness, and relationship to 
treatment. Adverse events will be coded by preferred term and system organ class using 
MedDRA version 20.0. Incidence of AEs will be summarized by treatment overall, by severity, 
and by relationship to study drug.  Serious AEs and AEs leading to discontinuation of study drug 
will also be presented. 
Vital sign, ECG with rhythm strip, and clinical laboratory results will be summarized by 
treatment. Physical examination findings will be listed. 
Pharmacokinetic Analyses 
Plasma concentrations and concentration-time data for dexmedetomidine will be used to 
calculate PK parameters; these data and results will be reported separately. Details regarding the 
analyses of PK data will be described in a separate PK SAP. The separate SAP for the PK 
analyses will be prepared and finalized prior to database lock. Data from subjects who 
participated in the study will be included in the pharmacokinetic analysis. Subjects with missing 
sample concentrations will be included in the pharmacokinetic analyses provided their 
pharmacokinetic parameters can be adequately characterized based upon the remaining data. 
Deviation from procedures described in this protocol that impact the quality of data required to 
meet the objectives of the study will be documented and may result in exclusion of 
pharmacokinetic data from the analyses for a particular subject. This includes any deviations or 
events that would invalidate the evaluation of the pharmacokinetics. Examples of deviations and 
events which could result in exclusion of pharmacokinetic data from the analyses include emesis 
after dosing (within the predetermined time), sample processing or assay errors that lead to 
inaccurate bioanalytical results. Other deviations or events, which do not disqualify data from 
analyses, may require minor adjustments to calculations. If these occur, data analyses will be 

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14. 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. 
14.1 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 sufficient 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 Conference on 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. 
14.2 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: 
1. The study site has received the appropriate IRB approval for the protocol and the appropriate 
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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. 
14.3 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. Confidentiality of records identifying the 
subject will be maintained. The Food and Drug Administration may inspect the records at any 
time. 
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 
 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. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central laboratory to the sponsor or its designee. A paper copy of the laboratory results will be 
provided to the study site and should be retained with each subject’s source data. 
14.4 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 

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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, 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. 
14.5 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 

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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’ 
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. 
14.6 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, 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. All records and documents pertaining to the study including, but not limited to those 
defined by GCP as essential will be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the drug. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or by an agreement with the Sponsor. It is the responsibility of the 
Sponsor to inform the Investigator/institution when these documents no longer need to be 
retained. To avoid any possible errors, the Investigator will contact the Sponsor before 
transferring or destroying any study records. The Investigator will also promptly notify the 
Sponsor in the event of accidental loss or destruction of any study records. 
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 study report to the regulatory authorities by the sponsor.   
 

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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. 
14.7 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. 
14.8 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. 

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15. FINAL CLINICAL STUDY REPORT 
The final study report will be written according to the “Guideline for Industry (Structure and 
Content of Clinical Study Reports)” from the International Conference on Harmonisation (ICH) 
E3. The final study report will present a narrative description of the clinical, analytical, 
pharmacokinetic, 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 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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