Clinical trial NCT04276883
Conditions: Agitation Associated With Bipolar Disorder Agitation,Psychomotor Bipolar Disorder
Sponsor: BioXcel Therapeutics Inc
Start date: 2020-02-24; Completion date: 2020-05-21
Enrollment: 380 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a definitive study to support the safety and efficacy evaluation of BXCL501 for the acute treatment of agitation in bipolar disorder. The BXCL501-302 study is designed to characterize the efficacy, safety and tolerability of BXCL501 (sublingual film formulation of DEX, HCl) in agitation associated with bipolar disorder.

Detailed description:
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. Male and female adults with acute agitation associated with bipolar disorder will be enrolled. Eligible subjects (acutely agitated subjects with bipolar disorder, generally hypomanic, manic or mixed episodes) 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. Efficacy and safety assessments will be conducted periodically before and after dosing.

Arms: arm 1: Sublingual film containing 120 Micrograms Dexmedetomidine arm 2: Sublingual film containing 180 Micrograms Dexmedetomidine arm 3: Sublingual placebo film
Interventions: intervention 1: Sublingual film containing Dexmedetomidine (BXCL501) intervention 2: Placebo Film
Intervention descriptions: intervention 1: Sublingual film containing Dexmedetomidine (BXCL501) intervention 2: Placebo Film for BXCL501

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
A Phase Ill Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Determine Efficacy and Safety 
of BXCL501 in Agitation Associated with Bipolar Dosorder 
NCT04276883 
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 
BIPOLAR DISORDER    
 
 
PROTOCOL NUMBER:  
BXCL501-302 
 
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 
administration9 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
YMRS 
 
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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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 
C-SSRS 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Buccal (SL) assessment 
for local irritation7 
 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
Likert Scales 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Likability Questions 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
Sampling8 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
Notes to the Schedule of Events: 
1 Pre-dose assessments will have a window of 60 minutes prior to dose with the exception of PEC and ACES which will be performed within 15 minutes of 
dosing (15 to 0 min). All post-dose assessments will have a window of -5/+15 minutes through the 1.5 hour assessments, -5/+25 minutes for the 2 hour 
assessments (with the exception of the PEC which will have a +/-5 minute window) and ± 30 minutes for the 4, 6 and 8 hour assessments and YMRS can be 
performed at any time. 
2 Safety Labs will include chemistry, hematology, urinalysis, UDS (local lab, only conducted at screening), alcohol breathalyzer (only conducted at screening), 
and urine pregnancy (only conducted at screening). Screening/enrollment labs: local labs drawn within 7 days prior to screening may suffice with the exception 
of urine drug screen. If results not available on the same day, a ‘desktop’ or non-CLIA test may be performed; to confirm, results from a CLIA-certified 
laboratory should be recorded once available. Central Labs should be performed on Screening, Day 3 and Day 7. 
3 ECG for pre-dose does not need to be repeated if screening ECG is conducted on the day of dosing. ECGs collected following treatment are to be performed 
prior to PK assessments. 
4 Resting (recumbent) vital signs (SBP, DBP and HR) will be taken upon having the subject recumbent for 5 min at Screening, Pre-dose and at 30 min, 1, 2, 4, 6, 
8 and 24 hours post dose, as well as Day 3 and Day 7. Triplicate measurements to be performed in case of Systolic BP <90 mmHg, Diastolic BP <60 mmHg or 
Pulse < 60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate) will be taken upon having the subject stand, with measurements taken after 1,3 and 
5 minutes and temperature will be taken at Screening, Pre-dose, 2, 4, 8 and 24 hours post first dose, as well as Day 3 and Day 7.  
5 PEC will be performed at Screening, Pre-dose (within 15 min prior to dose) and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6, 8 and 24 hours post dose. The PCRS must 
be performed prior to PEC rating, when required. ACES will be performed at Pre-dose (within 15 min of dose), 2, 4 and 8 hrs post dose. 
6 CGI-Severity will be performed at Screening and pre-dose. CGI-Improvement will be performed at 30 minutes, 1, 2 and 4 hours post dose. 
7 Buccal exam at 30 min, 2, 4 and 24hr post-dose for local irritation.  


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8 PK blood samples will be collected 1, 4, and 8 hr (while awake) after dose. A sample may not be collected if the Physician indicates in source documents that 
the patient is in a mental state that is not conducive to PK sample collection. Non-compliance or refusal of all or any PK draw will not be exclusionary nor result 
in ET. Vital signs are to be done prior to PK sample draws, when performed at the same timepoints.  
9 The investigator may choose to re-dose the patient after the 2 hour post-dose assessments are performed if the PEC change from baseline is < 40%. Patients can 
be re-dosed after completing the 2 hour post first dose assessments. Repeat dosing administers half of a film. Patients can be redosed twice in the 12 hour period 
post first dose . All assessments listed in this Schedule of Events at the 2 hour post first dose timepoint should be repeated at 2 hours post every re-dose. 
Assessments at 4, 6, or 8 hour post first dose that occur within 1 hour of a post re-dose assessment are not required to be performed.


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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 
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 ..........................................................................................28 
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 
11.1  Screening ...........................................................................................................31 


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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 
Young Mania Rating Scale (YMRS) ................................................................36 
Placebo-Control Reminder Script (PCRS) ........................................................36 
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 ........................................................................43 
Vital Signs .........................................................................................................43 
Electrocardiogram .............................................................................................44 
Pulse Oximetry ..................................................................................................44 
Physical Examination ........................................................................................44 
Concomitant Medications .................................................................................44 
Likert scales ......................................................................................................44 
Drug likability ...................................................................................................45 
13.  STATISTICAL METHODS .......................................................................................46 
13.1  General Considerations .....................................................................................46 


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13.2  Analysis Populations .........................................................................................46 
13.3  Statistical Analyses ............................................................................................46 
Subject Disposition and Demographic Characteristics .....................................46 
Efficacy Analyses .............................................................................................46 
Safety Analyses .................................................................................................48 
Pharmacokinetic Analyses ................................................................................48 
13.4  Sample Size Determination ...............................................................................49 
14.  STUDY CONDUCT ...................................................................................................50 
14.1  Sponsor and Investigator Responsibilities ........................................................50 
Sponsor Responsibilities ...................................................................................50 
Investigator Responsibilities .............................................................................50 
14.2  Site Initiation .....................................................................................................50 
14.3  Study Documents ..............................................................................................51 
Good Clinical Practice Documents ...................................................................51 
Case Report Forms ............................................................................................51 
Source Documents ............................................................................................52 
14.4  Data Quality Control .........................................................................................52 
Monitoring Procedures ......................................................................................52 
Data Management .............................................................................................53 
Quality Assurance/Audit ...................................................................................53 
14.5  Study Termination .............................................................................................53 
Regular Study Termination ...............................................................................53 
Premature Study Termination ...........................................................................53 
14.6  Study Site Closure .............................................................................................54 
Record Retention ...............................................................................................54 
Sample Retention ..............................................................................................54 
14.7  Changes to the Protocol .....................................................................................55 
14.8  Use of Information ............................................................................................55 
15.  FINAL CLINICAL STUDY REPORT ......................................................................56 
16.  ETHICAL AND LEGAL CONSIDERATIONS ........................................................57 
16.1  Declaration of Helsinki and Good Clinical Practice .........................................57 
16.2  Subject Information and Informed Consent ......................................................57 
16.3  Approval by Institutional Review Board ...........................................................57 
17.  REFERENCES ...........................................................................................................58 
 
 


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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-EC 
Positive and Negative Syndrome Scale – Excited Component 
PCRS 
Placebo-Control Reminder Script 
PD 
Pharmacodynamics 
PEC 
Positive and Negative Syndrome Scale – Excited Component 


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Abbreviation 
Definition 
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  
YMRS 
Young Mania Rating Scale 


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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 40 µg (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 different bipolar disorders but is predominantly associated with bipolar I 
disorder and is less frequently observed in bipolar II disorder. This study will enroll subjects with 
agitation associated with bipolar I or II disorder. Bipolar disorder, as defined by DSM-5, is 
subdivided into distinct disorders, the most common being bipolar I disorder, or bipolar II 
disorder. Bipolar I disorder is associated with at least one full episode of mania and possible 
additional episodes of full depression, occurring later in time or concurrently (“mixed episodes”). 
Bipolar II disorder is characterized by at least one episode of hypomania and at least one episode 
of major depression. Episodes in bipolar I and II disorders may be recurrent and progress in 
severity over time.  
As noted previously, agitation is a common occurrence in multiple psychiatric disorders, and 
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.  
 


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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 bipolar I or II disorder with hypomania, mania or 
mixed episodes 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 bipolar disorder. Patients meeting entry 
criteria will be randomized to 180µg BXCL501 or 120µg BXCL501 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. 
6.2 
Description 
Dexmedetomidine hydrochloride is the active S-enantiomer of medetomidine. BXCL501 is a 
sublingual film comprised of dexmedetomidine and the following inactive ingredients: 
Polyethylene Oxide, Hydroxypropyl Cellulose, Sucralose, Peppermint Oil, Emerald Green 
colorant, and FD&C Blue #1 colorant. 
No special transport or storage conditions are required for BXCL501. Packaged films can be 
stored at room temperature (25°C) and ambient humidity. 


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7. OBJECTIVES 
7.1 
Primary Endpoint 
The primary efficacy endpoint of the study will be the absolute change from baseline in the PEC 
total score at 2 hours. The intent to treat population will be analyzed and consists 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).  
 
7.2 Key Secondary Endpoint: 
The key secondary efficacy endpoint will be the earliest time where an effect on agitation is 
apparent as measured by change from baseline PEC total score in contrast with placebo.  
Exploratory endpoints include: 
1. Overall clinical improvement after drug administration as measured by the Clinical 
Global Impression – Improvement Scale (CGI-I) score. 
2. Agitation-Calmness Evaluation Scale (ACES) scores at 2, 4 and 8 hrs after dose 
administration.  
3. Change from baseline in total PEC score over time measured from 10 min through 24 
hrs after dosing.  
4. PEC Responders and CGI-I Responders at 2 hours following dose of BXCL501, 
compared with placebo:   
a. PEC responders will be defined as those who achieve at least a 40% reduction in 
PEC total score from baseline at or before 2 hours post-dose. 
b. CGI-I responders will be defined as subjects with a score of 1 or 2 on the CGI-I 
scale (the CGI-I non-responders will be defined as subjects with scores from 3 to 
7 at 2 hours).   
5. Time to rescue medication during the entire 24 hrs Post-treatment Evaluation Period for 
subjects receiving BXCL501 compared to placebo. 
6. Proportion of subjects per treatment group who received rescue medication by 4 hrs and 
within 24 hrs after dosing.  
7. Duration of calming effect as described by the change from baseline in PEC total score, 
and ACES score at 2, 4 and 8 hrs after dosing. 
8. Determine the safety profile of BXCL501 as measured by vital signs and treatment-
emergent adverse event reports.  
9. Describe the overall tolerability in terms of adverse event reports and local site 
(oral/sublingual) tolerability of oral film. 
10. Descriptive pharmacokinetics of BXCL501 in the patient population. 
11. Determine patient acceptability, taste and likability of study medication using likert 
scales to capture subject’s acceptability, opinion on taste and questions regarding 
likability. 
12. Characterize the patient population utilizing the Young Mania Rating Scale (YMRS). 


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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 bipolar I or II disorder will be 
enrolled.  
Eligible subjects (acutely agitated subjects with bipolar I or II 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 bipolar disorder.  The BXCL501-302 study is designed to characterize 
the efficacy, safety and tolerability of BXCL501 (sublingual film formulation of DEX, HCl) in 
agitation associated with bipolar 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 not bradycardic (must be greater than 60 


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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 in the assessment of 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 bipolar I or II 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. 
6. Patients who have hydrocephalus, seizure disorder, or history of significant head trauma, 
stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, 
meningitis, Parkinson’s disease or focal neurological findings. 


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7. History of syncope or other syncopal attacks, current evidence of hypovolemia, 
orthostatic hypotension (average of 1, 3 and 5 min measurements), a screening and 
baseline heart rate of < 55 beats per minutes or systolic blood pressure <110 mmHg or 
diastolic BP <70 mmHg. 
8. Patients with laboratory or ECG abnormalities considered clinically significant by the 
investigator or qualified designee [Advanced heart block (second-degree or above 
atrioventricular block without pacemaker), diagnosis of Sick sinus syndrome] that would 
have clinical implications for the patient's participation in the study.  
9. Patients with serious or unstable medical illnesses. These include current hepatic 
(moderate-severe hepatic impairment), renal, gastroenterologic, respiratory, 
cardiovascular (including ischemic heart disease, congestive heart failure), 
endocrinologic, or hematologic disease.  
10. Patients who have received an investigational drug within 30 days prior to the current 
agitation episode.  
11. Patients who are considered by the investigator, for any reason, to be an unsuitable 
candidate for receiving DEX; e.g. patients with a history of allergic reactions to DEX. 
9.4 
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 that 
is intolerable to the subject or otherwise considered unacceptable, for intolerable or unacceptable 
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, subjects will be randomized to 180µg BXCL501 or 120µg 
BXCL501 or placebo.  
Randomization will be 1:1:1 (180µg or 120µg BXCL501 or 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. 
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 


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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. 
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 
This study will be conducted under double-blind conditions so that neither the subject nor the 
Investigator or study staff members will know the identity of each subject’s treatment. BXCL501 
or placebo film will be provided to the subjects for self-administration under the supervision of a 
trained staff member. 
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 or project manager 
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 Treatment Compliance 
Drug accountability will be performed by site personnel and the drug administration compliance 
is expected to be 100%. 
10.9 Concomitant Medications 
All concomitant medications administered (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 study medication may be given at the discretion of the 
investigator. 
Permitted Therapies 
Concomitant medications are allowed (unless specifically prohibited) 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 PI or designee, rescue therapy with lorazepam po/IM 0.5-5 mg may be 
initiated as a standard of care treatment for acute agitation.  When rescue administration occurs, 
the time, dose and indication must be clearly recorded as ‘For agitation’ in CRF and source 
documents.  


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Medications for Insomnia 
Lorazepam or other benzodiazepines may be administered for insomnia. Administration may not 
occur sooner than 4 hrs after dosing of study treatment and the indication (Insomnia) must be 
clearly recorded in CRF and source documents. 
Prohibited Therapies 
The following medications are prohibited in the 4 hours before dosing of study treatment:  
Sedative/hypnotics, barbiturates, anxiolytics (including benzodiazepines), antihistamines (e.g. 
diphenhydramine), sedating antidepressants (mirtazapine, trazodone), triptans (e.g. sumatriptan), 
opioids. 
The following medications are prohibited from the time of screening until 4 hours post last dose, 
unless clinically indicated: 
Antiarrhythmics, Antibiotics/antifungals/antivirals, Anticholinergics, Anticonvulsants, 
Antipsychotics, Antihypertensive, Anxiolytics or sedative-hypnotics, Centrally acting calcium 
antagonist, Cholinomimetics, Migraine-Serotonin Receptor Agonist, Opioids.  
 
 


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11. STUDY PROCEDURES 
Subjects will provide written informed consent before any study-related procedures are initiated, 
including the cessation of 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 
 ECG with rhythm strip (not required if screening ECG is conducted on the day of dosing) 
 C-SSRS 
 YMRS 
 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 
 ACES 
 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 
 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. 


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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   
 YMRS 
 PCRS (prior to PEC) 
 PEC  
 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 
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. 


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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 bipolar disorder. 
Young Mania Rating Scale (YMRS) 
The YMRS is an 11-item scale evaluating mania symptoms based on the patient’s subjective 
report of their clinical condition. It will be used to characterize the patient population enrolled in 
the study. 
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. 
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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 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. 
 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 
12.2.1.1 Bioanalytical Sample Analyses 
A validated LC/MS/MS procedure will be used to measure plasma concentrations of 
dexmedetomidine (BXCL501). Samples from subjects who have at least one post-dose sample 
will be analyzed. 
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 will be presented. Representative chromatograms 
and standard curve graphs will 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 will be included in the final report. 
12.2.1.2 Bioanalytical Methodology 
The bioanalytical method, assay validation, and bioanalytical report for this study will be 
provided by the bioanalytical investigator.  Full validation of a sensitive assay for the appropriate 
analyte in biological fluid, including precision, accuracy, reproducibility, and selectivity will be 
included in the final report.  The bioanalytical report will include the stability of the frozen 
samples, limit of quantitation, recovery, and a summary of the standard curves. 
12.3 Safety 
Safety will be assessed during the study by the monitoring and recording of AEs, clinical 
laboratory test results (hematology, biochemistry, and urinalysis), vital sign measurements 
(systolic and diastolic blood pressures, heart rate measured as pulse, respiratory rate, and 
temperature), ECG, and physical examination findings. 
An independent data safety monitoring board (DSMB) will be chartered to review all SAEs and 
AE reports while the study remains blinded to the sponsor. The DSMB will meet regularly to 
evaluate the safety data. Should a known safety issue be identified (e.g. a high incidence of 
severe hypotension or bradycardia in the active 180µg dose arm or the 120µg arm), the DSMB 


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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 


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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. 
12.3.1.2 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 


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 Date of dose of study drug 
 Time and date of occurrence of the event 
 A brief description of the event, outcome to date, and any actions taken 
Within 24 hours of the initial notification, the investigator must e-mail a written SAE report form 
to the medical monitor/Safety team.  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). 
The following contact information is to be used for SAE reporting: 
 
BioXcel Therapeutics, Inc. SAE mailbox: Safety@bioxceltherapeutics.com and Cognitive 
Research Corporation: ekemper@cogres.com 
12.3.1.3.1 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: 
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.  Adverse events characterized as intermittent 
require documentation of onset and duration of each episode. 
12.3.1.3.2 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: 


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Not related: 
An AE with sufficient 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. 
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. 


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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). 
Local Labs (Screening only: To determine subject eligibility): 
Hematology: 
Consists of complete blood count (hemoglobin, hematocrit, 
white blood cell count with differential, red blood cell 
count, and platelet count) 
Serum chemistry: 
Includes blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase (serum 
glutamic-oxaloacetic transaminase), alanine 
aminotransferase (serum glutamic pyruvic transaminase), 
glucose, albumin, and total protein 
Urinalysis: 
Includes pH, specific gravity, protein, glucose, ketones, 
bilirubin, blood, nitrites, leukocytes, urobilinogen, 
microscopic urine analysis if dipstick positive 
Urine pregnancy test: 
Conducted for females of childbearing potential only (local 
only) 
Urine Drug Screen: 
Cocaine, amphetamine, phencyclidine, benzodiazepines, 
marijuana. (Note; marijuana positive is allowed provided 
subject is not moderately to severely dependent, 
benzodiazepine positive are allowed if prescribed)  
Alcohol breathalyzer: 
Only conducted at screening 
Central Labs (Screening, Day 3 and Day 7): 
Hematology: 
Consists of complete blood count (hemoglobin, hematocrit, 
white blood cell count with differential, red blood cell count, 
and platelet count) 
Serum chemistry: 
Includes blood urea nitrogen, creatinine, total bilirubin, alkaline 
phosphatase, aspartate aminotransferase (serum glutamic-
oxaloacetic transaminase), alanine aminotransferase (serum 
glutamic pyruvic transaminase), glucose, albumin, and total 
protein 
Urinalysis: 
Includes pH, specific gravity, protein, glucose, ketones, 
bilirubin, blood, nitrites, leukocytes, urobilinogen, microscopic 
urine analysis if dipstick positive 
 
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 (Table 3.1).  Measurements should be made 
at least 1 minute apart using the same arm at each visit. 


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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 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  during each study visit. 
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 


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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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post-dose in the BXCL501 120 µg group, and ∆PBO denotes the change from baseline in the PEC 
at 2 hours post-dose in the placebo group. These hypotheses, H01 and H02, 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 
and set at 0.025. The outcome variable for the MMRM will be the change from baseline in the 
PEC score at 10, 20, 30, 45, 60, 90, and 120 minutes and the following set of covariates: 
treatment group, baseline PEC, visit, baseline PEC by visit interaction term, and treatment group 
by visit interaction term. The test of the null hypothesis is obtained from a least squares mean 
analysis. A sensitivity analysis will be conducted to assess the impact of any missing data. 
Control-based, multiple imputation will be used to impute missing values based on the placebo 
group experience, with details of the sensitivity analysis provided in the SAP. 
The key secondary endpoints will be evaluated using the fixed-sequence method with the 
endpoints ordered in a hierarchy within each dosing group comparison with testing stopping 
once a significance level is greater than 0.025. The key secondary endpoints are as follows: 
1. Change from baseline in the PEC score at 90 minutes. 
2. Change from baseline in the PEC score at 60 minutes. 
3. Change from baseline in the PEC score at 45 minutes. 
4. Change from baseline in the PEC score at 30 minutes. 
5. Change from baseline in the PEC score at 20 minutes. 
6. Change from baseline in the PEC score at 10 minutes.  
 
Other exploratory endpoints include: 
1. Overall clinical improvement after drug administration as measured by the Clinical 
Global Impression – Improvement Scale (CGI-I) score 
2. Agitation-Calmness Evaluation Scale (ACES) scores at 2, 4 and 8 hrs after dose 
administration.  
3. Change from baseline in total PEC score over time measured from 10 min through 24 
hrs after dosing.  
4. PEC Responders and CGI-I Responders at 2 hours following dose of BXCL501, 
compared with placebo:   
a. PEC responders will be defined as those who achieve at least a 40% reduction in 
PEC total score from baseline at or before 2 hours post-dose. 
b. CGI-I responders will be defined as subjects with a score of 1 or 2 on the CGI-I 
scale (the CGI-I non-responders will be defined as subjects with scores from 3 to 
7 at 2 hours).   
5. Time to rescue medication during the entire 24 hrs Post-treatment Evaluation Period for 
subjects receiving BXCL501 compared to placebo. 
6. Number of subjects per treatment group who received rescue medication by 4 hrs and 
within 24 hrs after dosing.  
7. Duration of calming effect as described by the change from baseline in PEC total score 
at 4, 6, 8 and 24 hrs after dosing. 
8. Determine the safety profile of BXCL501 as measured by vital signs and treatment-
emergent adverse event reports and vital signs. 


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9. Describe the overall tolerability in terms of adverse event reports and local site 
(oral/sublingual) tolerability of oral film. 
10. Descriptive pharmacokinetics of BXCL501 in the patient population. 
11. Determine patient acceptability, taste and likability of study medication using Likert 
scales to capture subject’s acceptability, opinion on taste and questions regarding 
likability. 
12. Characterize the patient population utilizing the Young Mania Rating Scale (YMRS). 
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 
adjusted and documented accordingly such that conclusions are not biased. An example of such 
an event includes, but is not limited to, minor deviations between the actual and scheduled time 
of sample collection. 


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All pharmacokinetic parameters will be calculated using non-compartmental analysis using 
WinNonlin Version 5.2 or higher. Actual sampling times will be used in all pharmacokinetic 
analyses. Per protocol times will be used to calculate mean plasma concentrations for graphical 
displays. 
Other PK analyses may be performed as appropriate. 
13.4 Sample Size Determination 
The estimated sample size was estimated using information from the Phase 2  study regarding 
the standard deviation of the change from baseline in PEC score and the expected magnitude of 
this difference. Under the assumptions of a two-sided significance level of 0.025, a two-sample t-
test, a randomization ratio of 1:1, an assumed power of 0.90, and standard deviations of 4.0, 4.2, 
4.4, and 4.6. The estimated sample size per group is provided in Table 13.1 below. Table 13.12 
provides the estimated sample size per group for a power of 0.85. The observed difference 
between the BXCL501 and placebo groups in the 180µg group was 0.7, 3.5, 5.0, 6.0, and 6.2 at 
30, 45, 60, 90, and 120 minutes, respectively. With a sample size of approximately 375 subjects 
(125/group) the study is well powered to detect differences at 45 minutes or later.  
A blinded sample size recalculation will take place when approximately 50% of the information 
is 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. 
Table 13.1: 
Estimated Sample Size group for power of 0.90 
Estimated sample size/group for power of 0.90, a two-sided significance level of 0.025,  varying 
mean difference in change from baseline in PEC score, and standard deviations of the change 
from baseline in PEC score.  
 
 
 
 
 
Standard deviation 
Mean difference 
 
4.0 
 
4.2 
 
4.4 
 
4.6 
 
2.0 
 
101 
 
111 
 
122 
 
133 
 
1.9 
 
112 
 
123 
 
135 
 
147 
 
1.8 
 
124 
 
137 
 
150 
 
164 
 
1.7 
 
139 
 
153 
 
168 
 
184 
 
 
 
 
 
Table 13.2: 
Estimated Sample Size group for power of 0.85 
Estimated sample size/group for power of 0.85, a two-sided significance level of 0.025, varying 
mean difference in change from baseline in PEC score, and standard deviations of the change 
from baseline in PEC score. 
 
 
 
 
 
Standard deviation 
Mean difference 
 
4.0 
 
4.2 
 
4.4 
 
4.6 
 
2.0 
 
 88 
 
  97 
 
106 
 
115 
 
1.9 
 
 97 
 
107 
 
117 
 
128 
 
1.8 
 
108 
 
119 
 
130 
 
142 
 
1.7 
 
121 
 
133 
 
146 
 
159 
 
 
 
 
 
 


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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 
informed consent. 


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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. 


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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, 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 
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. 


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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.   
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 


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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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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. 
Allen MH, Feifel D, Lesem MD, Zimbroff DL, Ross R, Munzar P, Spyker DA, Cassella JV. 
Efficacy and Safety of Loxapine for Inhalation in the Treatment of Agitation in Patients with 
Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial. J Clin Psychiatry. 2011; 
72 (10): 1313-1321. 
Battaglia J. Pharmacological Management of Acute Agitation. Drugs. 2005; 65 (9): 1207-1222. 
Bellnier TJ. Continuum of Care: Stabilizing the Acutely Agitated Patient. Am J Health-Syst 
Pharm. 2002; 59 (Suppl 5): S12-8. 
Berk M, Dodd S. Efficacy of Atypical Antipsychotics in Bipolar Disorder. Drugs 2005; 65 (2): 
257-269. 
Conn DK, Lieff S. Diagnosing and Managing Delirium in the Elderly. Can Fam Physician. 2001; 
47: 101-108. 
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. 
Levin, Harvey S., Vincent M. O'donnell, and Robert G. Grossman. "The Galveston Orientation 
and Amnesia Test: A practical scale to assess cognition after head injury." Journal of Nervous 
and Mental Disease (1979). 
Lindenmayer JP. The Pathophysiology of Agitation. J Clin Psychiatry. 2000; 61 (Suppl 14): 5-
10. 
Meehan K, Zhang F, David S, Tohen M, Janicak P, Small J, Koch K, Rizk R, Walker D, Tran P, 
Breier A. A Double-Blind, Randomized Comparison of the Efficacy and Safety of Intramuscular 
Injections of Olanzapine, Lorazepam, or Placebo in Treating Acutely Agitated Patients 
Diagnosed with Bipolar Mania. Clin Psychopharmacol. 2001; 21: 389–397. 
Meehan KM, Wang H, David SR, Nisivoccia JR, Jones B, Beasley CM Jr, Feldman PD, Mintzer 
JE, Beckett LM, Breier A. Comparison of Rapidly Acting Intramuscular Olanzapine, Lorazepam, 
and Placebo: A Double-blind, Randomized Study in Acutely Agitated Patients with Dementia. 
Neuropsychopharmacology. 2002; 26: 494–504. 


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MHRA. CLH Report: Proposal for Harmonised Classification and Labelling, Substance Name: 
Medetomidine. October 2014. Version 1. 
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. 
Precedex. US Package Insert. 2016 May. 
Sanford M, Scott LJ. Intramuscular Aripiprazole a Review of its Use in the Management of 
Agitation in Schizophrenia and Bipolar I Disorder. CNS Drugs. 2008; 22 (4): 335-352. 

SAP_001.pdf: 
CONFIDENTIAL 
 
 
 
 
 
 
A Phase III Multicenter, Randomized, Double-blind, Placebo-
controlled Study to Determine Efficacy and Safety of BXCL501 in 
Agitation Associated with Bipolar Disorder 
 
NCT04276883 
 
4/1/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
 
BioXcel Therapeutics, Inc. 
 
 
Protocol BXCL501-302 
A Phase III Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Determine Efficacy and Safety 
of BXCL501 in Agitation Associated with Bipolar Disorder 
 
Statistical analysis plan 
 
 
 
 
 
 
 
Prepared by: 
 
 
 
 


CONFIDENTIAL 
 
Protocol BXCL501-302 
Statistical analysis plan 
Prepared by: 
 
 
 
Author: 
Date: 
April 1, 2020 
 
 
 
 
 
Approved by: BioXcel Therapeutics, Inc. 
 
 
 
Date: 
April 7, 2020 


CONFIDENTIAL 
 
BXCL501-302 STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page i 
 
 
Contents 
1. Introduction ....................................................................................................................................... 1 
2. Study objectives ................................................................................................................................. 1 
2.1. 
Primary objective .................................................................................................................... 1 
2.2. 
Key secondary objective ......................................................................................................... 1 
2.3. 
Exploratory objectives ............................................................................................................ 2 
3. Study design and conduct ............................................................................................................... 2 
3.1. 
Study design ............................................................................................................................ 2 
3.2. 
Study population .................................................................................................................... 2 
3.3. 
Study treatment ....................................................................................................................... 4 
3.4. 
Schedule of events .................................................................................................................. 4 
4. Outcome variable definitions .......................................................................................................... 8 
4.1. 
Screening and baseline characteristics ................................................................................. 8 
4.2. 
Efficacy assessments ............................................................................................................... 8 
4.2.1. 
Positive and Negative Syndrome Scale – Excited Component (PEC) ................ 8 
4.2.2. 
Clinical Global Impression–Severity (CGI-S) and Clinical Global Impression– 
Improvement (CGI-I) ................................................................................................ 8 
4.2.3. 
Agitation-Calmness Evaluation Scale (ACES) ....................................................... 9 
4.2.4. 
Young Mania Rating Scale (YMRS) ....................................................................... 10 
4.2.5. 
Likert scales .............................................................................................................. 10 
4.2.6. 
Drug likability .......................................................................................................... 10 
4.3. 
Efficacy endpoints ................................................................................................................ 10 
4.3.1. 
Primary endpoint .................................................................................................... 10 
4.3.2. 
Key secondary endpoints ....................................................................................... 11 
4.3.3. 
Exploratory endpoints ............................................................................................ 11 
4.4. 
Safety assessments ................................................................................................................ 12 
4.4.1. 
Adverse events ........................................................................................................ 13 
4.4.2. 
Columbia Suicide Severity Rating Scale (C-SSRS) .............................................. 13 


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Page ii 
Contents, continued 
4.4.3. 
Laboratory safety assessments ............................................................................... 13 
4.4.4. 
Vital signs ................................................................................................................. 14 
4.4.5. 
Electrocardiogram (ECG) ....................................................................................... 14 
4.4.6. 
Physical examinations ............................................................................................. 14 
4.4.7. 
Concomitant medications ....................................................................................... 15 
5. Database lock and unblinding ....................................................................................................... 15 
5.1. 
Blind review of selected data prior to final database lock ............................................... 15 
5.2. 
Final database lock ............................................................................................................... 15 
5.3. 
Authorization for unblinding .............................................................................................. 16 
6. Statistical analyses ........................................................................................................................... 16 
6.1. 
Statistical methodology ........................................................................................................ 16 
6.1.1. 
Sample size determination ..................................................................................... 16 
6.1.2. 
Analysis populations .............................................................................................. 17 
6.1.3. 
General considerations ........................................................................................... 17 
6.1.4. 
Procedures for handling missing data .................................................................. 18 
6.2. 
Demographics and baseline characteristics ....................................................................... 19 
6.3. 
Subject disposition ................................................................................................................ 19 
6.4. 
Efficacy analyses ................................................................................................................... 19 
6.4.1. 
Primary analysis ...................................................................................................... 20 
6.4.2. 
Key secondary analyses .......................................................................................... 22 
6.4.3. 
Exploratory analyses ............................................................................................... 23 
7. Safety analyses ................................................................................................................................. 26 
7.1. 
Adverse events ...................................................................................................................... 27 
7.2. 
Clinical laboratory evaluations ........................................................................................... 27 
7.3. 
Physical examination ............................................................................................................ 27 
7.4. 
Vital signs .............................................................................................................................. 27 
7.5. 
12-lead electrocardiogram ................................................................................................... 27 


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BXCL501-302 STATISTICAL ANALYSIS PLAN 
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Contents, continued 
7.6. 
Concomitant medications .................................................................................................... 28 
7.7. 
Buccal exam for local irritation ............................................................................................ 28 
8. References ........................................................................................................................................ 28 
9. Appendix .......................................................................................................................................... 29 
9.1. 
MMRM analysis .................................................................................................................... 29 
9.2. 
Methods for missing data .................................................................................................... 30 
9.2.1. 
Missing at random imputation .................................................................................. 32 
9.2.2. 
Control-based imputation ........................................................................................... 35 
Exhibits 
Exhibit 1.  Inclusion criteria ................................................................................................................... 3 
Exhibit 2.  Exclusion criteria .................................................................................................................. 3 
Exhibit 3.  Schedule of events ................................................................................................................ 5 
Exhibit 4.  Laboratory safety assessments ......................................................................................... 13 
Tables 
Table 1. 
Estimated sample size per group for power of 0.90, a two-sided significance 
level of 0.025, varying mean difference in change from baseline in PEC 
score, and varying standard deviations of the change from baseline in PEC 
score..................................................................................................................................... 17 
Table 2. 
Estimated sample size per group for power of 0.85, a two-sided significance 
level of 0.025, varying mean difference in change from baseline in PEC 
score, and varying standard deviations of the change from baseline in PEC 
score..................................................................................................................................... 17 
Table 3. 
Estimand attributes for the primary efficacy analysis ................................................. 19 


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BXCL501-302 STATISTICAL ANALYSIS PLAN 
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Tables, continued 
Table 4. 
Estimand attributes for the key secondary efficacy analysis ....................................... 23 
Table 5. 
SAS code for MMRM analysis ......................................................................................... 30 
Table 6. 
SAS code to create datasets satisfying monotone missing condition ......................... 31 
Table 7. 
SAS code for missing at random imputation ................................................................. 33 
Table 8. 
SAS code for MMRM analysis as part of the imputation process ............................... 34 
Table 9. 
SAS code for Rubin’s rule ................................................................................................. 34 
Table 10. 
SAS code for control-based imputation .......................................................................... 35 


CONFIDENTIAL 
 
BXCL501-302 STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page v 
 
 
Abbreviations 
 
ACES 
Agitation and Calmness Evaluation Scale 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BDR 
blind data review 
BMI 
body mass index 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CS 
cumulative sum 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
diastolic blood pressure 
DEX 
dexmedetomidine 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
hr 
hour 
ITT 
intent to treat 
IUD 
intrauterine device 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini-Mental State Examination 
MMRM 
mixed model repeated measures 
NCS 
normalized cumulative sum 
PEC 
Positive and Negative Syndrome Scale – Excited Component 
PK 
pharmacokinetic 
PP 
per protocol 
SAE 
serious adverse event 
SAF 
safety population 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
THC 
tetrahydrocannabinol 
UDS 
urine drug screen 
WHO 
World Health Organization 
YMRS 
Young Mania Rating Scale 
µg 
Microgram 


CONFIDENTIAL 
 
BXCL501-302 STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 1 
 
 
1. 
Introduction 
 
This statistical analysis plan (SAP) describes the planned analyses for BioXcel’s Protocol 
BXCL501-302, entitled “A Phase III Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Determine Efficacy and Safety of BXCL501 in Agitation 
Associated with Bipolar Disorder”. This SAP is based on version 3 of the protocol, dated 
January 31, 2020. 
 
This SAP is to be interpreted in conjunction with the protocol. Should the SAP and protocol be 
inconsistent with respect to the planned analyses, the language of the SAP is governing. If the 
final clinical study report (CSR) contains changes to any planned statistical analyses, the 
justification for any such differences will be fully documented in the CSR. 
 
2. 
Study objectives 
 
2.1. 
Primary objective 
 
The primary objective is to determine if a single dose of BXCL501 effectively reduces 
symptoms of acute agitation associated with bipolar disorder assessed using the Positive and 
Negative Syndrome Scale (PANSS) – Excited Component (PEC) change from baseline as 
compared to placebo. 
 
The corresponding primary efficacy endpoint is the absolute change from baseline in the PEC 
total score at 2 hours. This analysis will use the intent to treat (ITT) population, which consists 
of all subjects who take any study medication and who had both baseline and at least one 
efficacy assessment after dosing. Observations will continue to be recorded after use of rescue 
medication although these will be censored (considered missing) in the analyses. 
 
2.2. 
Key secondary objective 
 
The key secondary objective is to determine the earliest time at which an effect on agitation is 
apparent as measured by change from baseline in PEC total score. 


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BXCL501-302 STATISTICAL ANALYSIS PLAN 
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Page 2 
 
 
2.3. 
Exploratory objectives 
 
Exploratory objectives are to further determine the efficacy, safety, tolerability, and 
pharmacokinetics (PK) of BXCL501 in patients with acute agitation associated with bipolar 
disorder, including to: 
 determine the overall clinical improvement after drug administration as measured 
by the Clinical Global Impression–Improvement Scale (CGI-I); 
  describe the duration of calming as measured by the PEC and Agitation and 
Calmness Evaluation Scale (ACES); 
 determine the safety profile of BXCL501 as measured by report of adverse events 
(AEs) and vital signs; 
 describe the overall tolerability in terms of treatment-emergent AE reports and local 
site (oral/sublingual) tolerability of oral film; 
 describe the subject’s opinion on taste, acceptability, and likability of study 
medication; and 
  characterize the patient population utilizing the Young Mania Rating Scale (YMRS). 
 
3. 
Study design and conduct 
 
3.1. 
Study design 
 
This is a randomized, double-blind, placebo-controlled Phase III study assessing the efficacy, 
safety, and tolerability of BXCL501 in adult (18–75 years old) males and females with acute 
agitation associated with bipolar disorder. This is an in-clinic study. 
 
3.2. 
Study population 
 
This study will enroll approximately 375 subjects at up to 30 sites in the United States. Eligible 
subjects will be randomized in a 1:1:1 ratio to receive BXCL501 180µg, BXCL501 120µg, or 
matching placebo film. Study randomization will be computer generated based on a permuted 
block design stratified by age (<65 versus ≥65 years old). At the time of the writing of this SAP, 
no subjects over the age of 65 have been enrolled in the trial. 
 
Exhibit 1 and Exhibit 2 display the study’s inclusion and exclusion criteria, respectively. 


CONFIDENTIAL 
 
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Exhibit 1. Inclusion criteria 
 
1. Male and female patients between the ages of 18 to 75 years, inclusive. 
2. Patients who have met DSM-5 criteria for bipolar I or II 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 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 electrocardiogram (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. 
 
 
 
Exhibit 2. Exclusion 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 or 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. 
6. Patients who have hydrocephalus, seizure disorder, or history of significant head trauma, 
stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, 
meningitis, Parkinson’s disease or focal neurological findings. 
7. History of syncope or other syncopal attacks, current evidence of hypovolemia, orthostatic 
hypotension (average of 1, 3, and 5 minute measurements), a baseline heart rate of <55 beats 
per minutes or systolic blood pressure <110 mmHg or diastolic blood pressure (BP) 
<70 mmHg. 
 


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Exhibit 2. Exclusion criteria, continued 
 
8. Patients with laboratory or ECG abnormalities considered clinically significant by the 
investigator or qualified designee (advanced heart block [second-degree or above 
atrioventricular block without pacemaker], diagnosis of sick sinus syndrome) that would 
have clinical implications for the patient's participation in the study. 
9. Patients with serious or unstable medical illnesses. These include current hepatic 
(moderate–severe hepatic impairment), renal, gastroenterologic, respiratory, cardiovascular 
(including ischemic heart disease, congestive heart failure), endocrinologic, or hematologic 
disease. 
10. Patients who have received an investigational drug within 30 days prior to the current 
agitation episode. 
11. Patients who are considered by the investigator, for any reason, to be an unsuitable 
 
candidate for receiving DEX; e.g. patients with a history of allergic reactions to DEX. 
 
 
 
3.3. 
Study treatment 
 
BXCL501 is a thin film formulation of dexmedetomidine (DEX) for sublingual administration. 
Dosing delivers 180µg or 120µg of DEX sublingually. The duration of treatment (BXCL501 or 
placebo) is one day. 
 
3.4. 
Schedule of events 
 
Exhibit 3 displays the schedule of events and assessments. 


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Exhibit 3. Schedule of events 
 
 
 
Screening 
 
Day 1 treatment evaluation 
Pre-dose1 
 
Post-dose1 
Day 2 (+1) 
follow-up 
Day 3 
discharge 
Day 7 (+2) 
end of study 
 
 
 
Informed consent 
× 
Medical history 
Demographics 
Weight 
Height 
BMI 
Alcohol 
breathalyzer 
MINI 
Physical exam 
Safety labs2 
ECG with 
rhythm strip3 
Pulse oximetry 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
1. 
Pre-dose assessments will have a window of 60 minutes prior to dose with the exception of PEC and ACES which will be performed within 15 minutes of dosing (15 to 0 min). All 
post-dose assessments will have a window of -5/+15 minutes through the 1.5 hour assessments, -5/+25 minutes for the 2 hour assessments (with the exception of the PEC which will 
have a +/-3 minute window) and ± 30 minutes for the 4, 6 and 8 hour assessments, and YMRS can be performed at any time. 
2. 
Safety Labs will include chemistry, hematology, urinalysis, UDS (local lab)(only conducted at Screening), alcohol breathalyzer (only conducted at Screening), and urine pregnancy 
(only conducted at Screening). Screening/enrollment labs: local labs drawn within 7 days prior to Screeningmay suffice with the exception of urine drug screen. If results not 
available on the same day, a ‘desktop’ or non-CLIA test may be performed; to confirm, results from a CLIA-certified laboratory should be recorded once available. Central Labs 
should be performed on Screening, Day 3 and Day 7. 
3. 
ECG for pre-dose does not need to be repeated if Screening ECG is conducted on the day of dosing. ECGs collected following treatment are to be performed prior to PK 
assessments. 
(page 1 of 3) 
-1 hr to 
10 
20 
30 
45 
1.5 
24 hr 
Timepoint 
Pre-treatment 
time 0 
min 
min 
min 
min 
1 hr 
hr 
2 hr 
4 hr 
6 hr 
8 hr 
(-9/+12 hr) 


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Exhibit 3. Schedule of events, continued 
 
 
 
Screening 
 
Day 1 treatment evaluation 
Pre-dose1 
 
Post-dose1 
Day 2 (+1) 
follow-up 
Day 3 
discharge 
Day 7 (+2) 
end of study 
 
 
 
Resting vital 
signs4 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Orthostatic vital 
signs4 
× 
× 
× 
× 
× 
× 
× 
× 
Admit to unit 
× 
Inclusion/ 
exclusion criteria 
× 
× 
Randomization 
× 
Study drug 
administration9 
× 
YMRS 
× 
× 
PCRS5 
× 
× 
× 
× 
PEC5 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
ACES5 
× 
× 
× 
× 
4. 
Resting (recumbent) vital signs (SBP, DBP and HR) will be taken upon having the subject recumbent for 5 min at Screening, Pre-dose and at 30 min, 1, 2, 4, 6, 8 and 24 
hours post dose. Triplicate measurements to be performed in case of Systolic BP <90 mmHg, Diastolic BP <60 mmHg or Pulse <60 bpm. Orthostatic measurements (SBP, 
DBP, HR, respiratory rate) will be taken upon having the subject stand, with measurements taken after 1, 3, and 5 minutes and temperature will be taken at Screening, 
Pre-dose, 2, 4, 8, and 24 hours post–first dose, as well as Day 3 and Day 7. 
5. 
PEC will be performed at Screening, Pre-dose (within 15 min prior to 1st dose) and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6, 8 and 24 hours post dose. The PCRS must be 
performed prior to PEC rating, when required. ACES will be performed at Pre-dose (within 15 min of dose), 2 and 4 hours post dose. 
9. 
The investigator may choose to re-dose the patient after the 2 hour post-dose assessments are performed if the PEC change from baseline is < 40%. Patients can be re- 
dosed after completing the 2 hour post first dose assessments. Repeat dosing administers half of a film. Patients can be redosed twice in the 12 hour period post first dose 
. All assessments listed in this Schedule of Events at the 2 hour post first dose timepoint should be repeated at 2 hours post every re-dose. Assessments at 4, 6, or 8 hour 
post first dose that occur within 1 hour of a post re-dose assessment are not required to be performed.” 
(page 2 of 3) 
-1 hr to 
10 
20 
30 
45 
1.5 
24 hr 
Timepoint 
Pre-treatment 
time 0 
min 
min 
min 
min 
1 hr 
hr 
2 hr 
4 hr 
6 hr 
8 hr 
(-9/+12 hr) 


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Exhibit 3. Schedule of events, continued 
 
 
Screening 
 
Day 1 treatment evaluation 
Pre-dose1 
 
Post-dose1 
Day 2 (+1) 
follow-up 
Day 3 
discharge 
Day 7 (+2) 
end of study 
Pre- 
-1 hr to 
10 
20 
30 
45 
1.5 
24 hr 
Timepoint 
treatment 
time 0 
min 
min 
min 
min 
1 hr 
hr 
2 hr 
4 hr 
6 hr 
8 hr 
(-9/+12 hr) 
 
CGI-S6 
× 
× 
CGI-I6 
× 
× 
× 
× 
C-SSRS 
× 
× 
× 
× 
Buccal (SL) 
assessment for local 
irritation7 
× 
× 
× 
× 
Likert scales 
× 
Likability questions 
× 
PK sampling8 
× 
× 
× 
Concomitant 
medications 
× 
× 
× 
× 
× 
× 
Adverse events 
× 
× 
× 
× 
× 
× 
6. 
CGI-Severity will be performed at Screening and pre-dose. CGI-Improvement will be performed at 30 minutes, 1, 2, and 4 hours post dose. 
7. 
Buccal exam at 30 min, 2, 4, and 24 hours post-dose for local irritation performed by blinded staff. 
8. 
PK blood samples will be collected 1, 4, and 8 hours (while awake) after dose. A sample may not be collected if the Physician indicates in source documents that the 
patient is in a mental state that is not conducive to PK sample collection. Non-compliance or refusal of all or any PK draw will not be exclusionary nor result in ET. Vital 
signs are to be done prior to PK sample draws, when performed at the same timepoints. 
(page 3 of 3) 


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4. 
Outcome variable definitions 
 
4.1. 
Screening and baseline characteristics 
 
Screening characteristics: Inclusion/exclusion criteria, demographic characteristics of age, sex, 
race, ethnicity, height, weight and body mass index (BMI), medical history, prior and 
concomitant medications, physical examination, resting and orthostatic vital signs, pregnancy 
test, 12-lead ECG, clinical laboratory results, urine drug screen, alcohol screen, Mini-Mental 
State Exam (MINI), PEC, Clinical Global Impression–Severity (CGI-S), and Columbia-Suicide 
Severity Rating Scale (C-SSRS) will be collected at Screening. 
 
Baseline characteristics: Eligibility, resting and orthostatic vital signs, adverse events, 
concomitant medications, CGI-S, PEC, ACES, and pharmacokinetic (PK) sampling will be 
collected prior to dose administration. 
 
4.2. 
Efficacy assessments 
 
The effect of study drug will be evaluated using several validated instruments as described 
below. 
 
4.2.1. 
Positive and Negative Syndrome Scale – Excited Component (PEC) 
 
Assessment of drug effect on acute agitation will be done using the PEC. The PEC comprises 
five items associated with agitation, each scored from 1 (minimum) to 7 (maximum): poor 
impulse control, tension, hostility, uncooperativeness, and excitement. The PEC is the sum of 
these 5 subscales and thus ranges from 5 to 35. 
 
4.2.2. 
Clinical Global Impression–Severity (CGI-S) and Clinical Global Impression–Improvement 
(CGI-I) 
The CGI-S will be based on the severity of agitation at Screening and pre-dose (immediately 
prior to start of dosing). The CGI-S scores will assess the severity of illness based on the 
following scale: 
• 
0 = not assessed 


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• 
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 CGI-I. It will be performed at 30 minutes, 
1 hour, 2 hours, and 4 hours 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 
• 
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 bipolar disorder. 
 
4.2.3. 
Agitation-Calmness Evaluation Scale (ACES) 
 
The ACES is a single-item measure rating overall agitation and sedation from 1 to 7: 
• 
1 = marked agitation 
• 
2 = moderate agitation 
• 
3 = mild agitation 
• 
4 = normal behavior 
• 
5 = mild calmness 
• 
6 = moderate calmness 


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BXCL501-302 STATISTICAL ANALYSIS PLAN 
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• 
7 = marked calmness 
• 
8 = deep sleep 
• 
9 = unarousable 
 
4.2.4. 
Young Mania Rating Scale (YMRS) 
 
The YMRS is an 11-item scale evaluating mania symptoms based on the patient’s subjective 
report of their clinical condition. It will be used to characterize the patient population enrolled 
in the study. 
 
4.2.5. 
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 this medication” and “The medication is 
acceptable” using a five-level Likert scale: 
• 
Strongly disagree 
• 
Disagree 
• 
Neither agree nor disagree 
• 
Agree 
• 
Agree strongly 
 
4.2.6. 
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. 
 
4.3. 
Efficacy endpoints 
 
4.3.1. 
Primary endpoint 
 
The primary efficacy endpoint for this study is the absolute change in the PEC total score from 
baseline to two hours following dose administration. 


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4.3.2. 
Key secondary endpoints 
 
If the primary endpoint is found to be statistically significant, key secondary endpoints will be 
evaluated using the fixed-sequence method, with the endpoints ordered in a hierarchy in 
which testing is stopped once a significance level within a given dose is greater than 0.025. 
Thus, if the significance level associated with the analysis of a key secondary endpoint is 
greater than 0.025, then all significance levels associated with the remaining key secondary 
endpoints for that dose will be nominal. The key secondary efficacy endpoints, which are 
measured following dose administration with no rescue medication administered during the 
two-hour period, will be tested in the following order: 
 Change from baseline in the PEC score at 90 minutes 
 Change from baseline in the PEC score at 60 minutes 
 Change from baseline in the PEC score at 45 minutes 
 Change from baseline in the PEC score at 30 minutes 
 Change from baseline in the PEC score at 20 minutes 
  Change from baseline in the PEC score at 10 minutes 
 
4.3.3. 
Exploratory endpoints 
 
The exploratory endpoints for this study are: 
 Overall clinical improvement after drug administration as measured by the CGI-I 
score. 
  ACES scores at 2, 4, and 8 hours after dose administration. 
 Change from baseline in total PEC score over time measured from 10 minutes 
through 24 hours after dosing. 


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 PEC responders and CGI-I responders at 2 hours following dose of BXCL501, 
compared with placebo: 
a. PEC responders will be defined as those who achieve at least a 
40% reduction in PEC total score from baseline at or before 2 hours 
post-dose. 
b. CGI-I responders will be defined as subjects with a score of 1 or 2 on the 
CGI-I scale (the CGI-I non-responders will be defined as subjects with 
scores from 3 to 7 at 2 hours). 
 Time to rescue medication during the entire 24 hours post-treatment evaluation 
period for subjects receiving BXCL501 compared to placebo. 
  Number of subjects per treatment group who received rescue medication by 4 hours 
and within 24 hours after dosing. 
  Duration of calming effect as described by the change from baseline in PEC total 
score, and ACES score at 2, 4, and 8 hours after dosing. 
 Determine the safety profile of BXCL501 as measured by treatment-emergent AE 
reports and vital signs. 
 Describe the overall tolerability in terms of AE reports and local site (oral/sublingual) 
tolerability of oral film. 
 Descriptive pharmacokinetics of BXCL501 in the patient population. 
 Determine patient acceptability, taste and likability of study medication using Likert 
scales to capture subject’s acceptability, opinion on taste, and questions regarding 
likability. 
 Characterize the patient population utilizing the YMRS. 
 
4.4. 
Safety assessments 
 
Safety will be assessed during the study by the monitoring and recording of AEs, clinical 
laboratory test results (hematology, biochemistry, and urinalysis), vital sign measurements 
(systolic and diastolic blood pressures, heart rate measured as pulse, respiratory rate, and 
temperature), ECG, and physical examination findings. 


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4.4.1. 
Adverse events 
 
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 relation 
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. 
 
4.4.2. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a suicidal ideation rating scale that identifies behaviors and thoughts that are 
associated with an increased risk of suicidal actions in the future. The C-SSRS 
Baseline/Screening version will be conducted at Screening. The C-SSRS Since Last Visit version 
will be conducted 24 hours post-dosing and at discharge. 
 
4.4.3. 
Laboratory safety assessments 
 
Exhibit 4 presents the laboratory tests that will be collected at the timepoints specified in the 
schedule of events (Exhibit 3). 
 
Exhibit 4. Laboratory safety assessments 
 
Hematology 
Complete blood count (hemoglobin, hematocrit, white blood cell count 
with differential, red blood cell count, and platelet count) 
Serum chemistry 
Blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, 
aspartate aminotransferase, alanine aminotransferase, glucose, 
albumin, and total protein 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, 
leukocytes, urobilinogen, microscopic urine analysis if dipstick positive 
Urine pregnancy test* 
Conducted for females of childbearing potential only 
Urine drug screen* 
Cocaine, amphetamine, phencyclidine, ketamine, benzodiazepines, 
marijuana. (Note: Marijuana positive is allowed provided subject is not 
moderately or severely dependent. Benzodiazepine positive is allowed 
if prescribed.) 
 Alcohol breathalyzer* 
 
*Conducted at Screening only 


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4.4.4. 
Vital signs 
 
Resting vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and 
heart rate (measured as pulse) will be measured after the subject has been in a sitting or supine 
position for at least five minutes at the timepoints specified in the schedule of events 
(Exhibit 3). Measurements should be made at least one minute apart using the same arm at 
each visit. 
 
At indicated timepoints, orthostatic measurement of systolic blood pressure, diastolic blood 
pressure, and heart rate will be measured after the subject has been standing for a total of 
five minutes. Temperature and respiratory rate will be recorded when orthostatic 
measurement is indicated in the schedule of events and are not required to be measured at 
resting vital sign timepoints. 
 
If the first measurement of vital signs (SBP, DBP, and pulse) shows SBP <90 mmHg, DBP 
<60 mmHg, or pulse <60 bpm, vital signs will be measured again in triplicate (same arm, 
separated by at least 1 minute). 
 
4.4.5. 
Electrocardiogram (ECG) 
 
A 12-lead ECG with rhythm strip will be performed at Screening, pre-dose, 2 hours, and 
24 hours post-dose. 
 
4.4.6. 
Physical examinations 
 
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 on the 
day of discharge. 


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4.4.7. 
Concomitant medications 
 
Concomitant medications will be reviewed and documented each day during the study. 
 
5. 
Database lock and unblinding 
 
5.1. 
Blind review of selected data prior to final database lock 
 
The clinical database will undergo a “soft lock” when (1) all patients have completed their 
Day 7 End of Study visit and (2) the database is nearly clean. After the soft data lock and prior 
to accessing the randomized treatment assignments, the following series of tables, listings, and 
figures will be generated without treatment assignments: 
• 
A listing of all efficacy outcome values 
• 
A listing of all subjects that indicates their inclusion in, or the reasons for their 
exclusion from, each analysis population 
• 
A listing of unanticipated cases of study drug exposure (e.g., placebo for patients 
who were randomized to BXCL501) 
• 
Resolution of other last-minute ambiguities related to the primary and secondary 
efficacy outcomes 
 
These blind data review (BDR) documents will provide the basis for a data review in order to 
finalize the primary and secondary outcomes and the analysis populations. BioXcel will 
document approval of the BDR minutes prior to the final database lock. 
 
5.2. 
Final database lock 
 
After completion of all BDR procedures, validation of the project databases and BioXcel’s 
approval of the BDR, the clinical database will be locked. After the database lock and the 
authorization for unblinding, the treatment codes will be merged to the analysis datasets. Any 
change to the clinical database after this time will require written authorization, with 
explanation, by BioXcel. In addition, beginning at the time of the database lock, an audit trail 
will be maintained for all versions of the analysis datasets that may result from refinements of 
the algorithms for derived variables in the course of the analysis. 


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5.3. 
Authorization for unblinding 
 
After the database lock and upon receipt of written authorization from BioXcel, a blinded 
study team will receive the actual treatment codes directly from the group maintaining the 
interactive web response system (IWRS). This team will generate top-line results and provide 
them to BioXcel. BioXcel will not have direct access to the randomized treatment codes until 
they have been provided the top-line results and datasets. 
 
6. 
Statistical analyses 
 
Statistical analyses will be performed using SAS® software version 9.4. 
 
6.1. 
Statistical methodology 
 
6.1.1. 
Sample size determination 
 
The sample size for this study was estimated using information from BXCL501-102 (the 
Phase Ib study of BXCL501) regarding the standard deviation of the change from baseline in 
PEC score and the expected magnitude of this difference. As two dose groups (180µg and 
120µg) will be compared to the placebo group, a two-sided significance level of 0.025 will be 
used for each comparison, resulting in an overall significance of 0.05. Assuming a two-sided 
significance level of 0.025, a two-sample t-test, a randomization ratio of 1:1:1, an assumed 
power of 0.90, and standard deviations of 4.0, 4.2, 4.4, and 4.6, the estimated sample size per 
group is provided in Table 1 below. Table 2 provides the estimated sample size per group for a 
power of 0.85. The observed difference between the BXCL501 and placebo groups in the 180µg 
group in the Phase Ib study was 0.7, 3.5, 5.0, 6.0, and 6.2 at 30, 45, 60, 90, and 120 minutes, 
respectively. With a sample size of at least 375 subjects (125 per group), this study is well 
powered to detect differences at 45 minutes or later. 


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Table 1. Estimated sample size per group for power of 0.90, a two-sided significance level of 
0.025, varying mean difference in change from baseline in PEC score, and varying 
standard deviations of the change from baseline in PEC score 
 
Standard deviation 
Mean difference 
4.0 
4.2 
4.4 
4.6 
2.0 
101 
 
111 
122 
133 
1.9 
112 
123 
135 
147 
1.8 
124 
137 
150 
164 
1.7 
139 
153 
168 
184 
 
 
Table 2. Estimated sample size per group for power of 0.85, a two-sided significance level of 
0.025, varying mean difference in change from baseline in PEC score, and varying 
standard deviations of the change from baseline in PEC score 
 
Standard deviation 
Mean difference 
4.0 
4.2 
4.4 
4.6 
2.0 
88 
 
97 
106 
115 
1.9 
97 
107 
117 
128 
1.8 
108 
119 
130 
142 
1.7 
121 
133 
146 
159 
 
 
6.1.2. 
Analysis populations 
 
The following populations are planned: 
• 
Safety population (SAF): 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 
 
6.1.3. 
General considerations 
 
The protocol-specified time windows for a visit and time of a measurement determine the visit 
assignment for each observation. Listings will present, by patient number and measurement 


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BXCL501-302 STATISTICAL ANALYSIS PLAN 
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time, all data collected on electronic case report forms (eCRFs), results analyzed by the central 
laboratory, parameters calculated from activity monitors, plasma concentrations, and other 
biomarker results. 
 
The same number of decimal places as in the raw data will be presented when reporting 
minimum and maximum. One more decimal place than in the raw data will be presented 
when reporting mean and standard deviation. 
 
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. 
 
All statistical testing will be based on a two-sided significance level of 0.025 unless otherwise 
stated. 
 
Data listings will be provided for all subjects up to the point of withdrawal. 
 
Baseline will be defined as the value collected at the pre-dose timepoint. Should this value be 
unavailable, the Screening value will be used. Instead of relying solely on visit labels in the 
clinical database for post-baseline values, results collected at a particular time will be 
attributed to a specific time point by calculating the time relative to randomization. Listings 
will present all measurements. 
 
For visits (or events) that occur on or after randomization, time is defined as: 
time = time of assessment – pre-dose time (time 0) 
 
For listings (such as for AEs), the quantity “time since first dose” is defined as: 
time since first dose = event time – time of first dose (time 0) 
 
6.1.4. 
Procedures for handling missing data 
 
Multiple imputation will be used to handle missing data. Details are provided in Section 6.4.1. 


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6.2. 
Demographics and baseline characteristics 
 
The following demographics and baseline characteristics will be presented in summary tables 
by treatment for the safety population: : demographic characteristics (age, sex, race, ethnicity), 
weight, height, BMI, medical history, prior medications, laboratory examinations, vital signs, 
and ECG. 
 
6.3. 
Subject disposition 
 
Subject disposition will include the number of subjects who enroll in the study and the 
number and percentage of subjects included in each analysis population by treatment. 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. 
 
6.4. 
Efficacy analyses 
 
The efficacy analysis will be conducted within the estimand framework. A summary of the 
attributes of the estimand is provided in Table 3. 
 
Table 3. 
Estimand attributes for the primary efficacy analysis 
 
Estimand attribute 
Description of attribute 
 
 
 
Target population 
ITT population—All patients who take any study medication 
and who had both baseline and at least one efficacy 
assessment after dosing 
Primary endpoint 
Absolute change from baseline in the total PEC total score at 
120 minutes 
Handling of intercurrent events 
All values collected after the use of rescue treatment and 
withdrawal from study will be set to missing. 
Population-level summary 
Difference between dose-specific treatment arm and placebo 
arm in mean change from baseline in the total PEC score using 
 
all measurements from baseline through 120 min 
 


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The trial product estimands are defined as: 
• 
The difference in the mean change from baseline through 120 minutes in the total 
PEC scores between the BXCL501 180µg arm and the placebo arm in the ITT 
population for subjects who did not use rescue medication. 
• 
The difference in the mean change from baseline through 120 minutes in the total 
PEC scores between the BXCL501 120µg arm and the placebo arm in the ITT 
population for subjects who did not use rescue medication. 
 
The null and alternative hypotheses to be tested for these estimands are 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 score at 2 hours post-dose in the 
BXCL501 180µg group, ∆BXCL501_120 denotes the change from baseline in the PEC score at 
2 hours post-dose in the BXCL501 120µg group, and ∆PBO denotes the change from baseline in 
the PEC at 2 hours post-dose in the placebo group. These hypotheses, H01 and H02, 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 and set at 0.025. For the analysis of the key secondary endpoints, a 
Bonferroni correction will be applied with testing for each hypothesis using a significance level 
of 0.025. A fixed sequence approach will then be used to adjust for the multiple testing at each 
timepoint as described in Section 4.3.2. 
 
6.4.1. 
Primary analysis 
 
The primary efficacy endpoint is the absolute change from baseline in the PEC total score at 
2 hours in the ITT population as described in Table 3. The population-level summary is the 
difference between the BXCL501 180µg and placebo arms and the difference between the 
BXCL501 120µg and placebo arms in the mean absolute change from baseline in the PEC total 
score at 2 hours. These differences will be estimated using a MMRM as described below. 
 
The MMRM will be fit with change from baseline as the outcome at each of the following 
timepoints: 10, 20, 30, 45, 60, 90, and 120 minutes. The covariates included in the model are as 


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follows: baseline PEC score, age stratum, study site, visit, treatment group (BXCL501 180µg, 
BXCL501 120µg, placebo), baseline PEC score by visit interaction term, and treatment group 
by visit interaction term. The model will be fit using restricted maximum likelihood with an 
unstructured covariance matrix and the Kenward-Roger approximation for the computation of 
the degrees of freedom. If the MMRM with an unstructured covariance matrix does not 
converge, the following covariance structures will be substituted, in the order listed below. 
Each subsequent covariance structure will be used only if each previous covariance structure 
was used and no previous model converged. 
 Heterogenous Toeplitz covariance structure (assuming different variances at each 
time point and that measurements taken closer together in time are more highly 
correlated than those taken farther apart). 
 Toeplitz covariance structure (assuming measurements taken closer together in time 
are more highly correlated than those taken farther apart). 
 First order auto-regressive (AR[1]) covariance structure (assuming measurements 
taken closer together in time are more highly correlated than those taken farther 
apart, but more constrained than the Toeplitz structure). 
 Compound symmetry covariance structure (assuming equal correlation for 
measurements from a patient, regardless of how far apart in time when they were 
taken). 
 
There are two tests of interest: the comparison of the BXCL501 180µg group to placebo and the 
comparison of the BXCL501 120µg group to placebo. The estimated mean difference between 
the group treated with either BXCL501 180µg or 120µg and the placebo group in change from 
baseline in the PEC score will be estimated at 2 hours. The details of the SAS code for this 
analysis are provided in the Appendix of this SAP (Section 9.1). The SAS code presented in 
this SAP may be modified based on test data from the trial when a separate set of 
programming specifications will be developed. 
 
There was little missing data in the Phase 2 study of BXCL501, and the expectation is that 
missing data will not be an issue in this study. However, methods to account for missing data 


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may be needed in this study, so a plan for the handling of missing data is pre-specified in this 
SAP using multiple imputation. Sensitivity analyses will be performed based on missing at 
random multiple imputation, in which imputed values are based on the treatment group to 
which the subject is randomized, and based on control-based imputation, in which imputed 
values are obtained from the placebo data rather than the treatment group to which the subject 
is randomized. Monotone missing imputation will be used as the method of choice with 
100 imputed datasets derived for the missing at random approach, and missing not at random 
imputation will be used for the control-based approach. All results will be summarized in 
tables and a forest plot. Details are provided in the Appendix of this SAP (Section 9.2) to be 
finalized before the blinded data review. This code will need to be vetted on a blinded test set 
of data from the trial during the development of the programming specifications for this SAP. 
 
6.4.2. 
Key secondary analyses 
 
In addition to the primary efficacy endpoint, PEC scores for each of the comparisons of 
BXCL501 180µg or 120µg to placebo will be summarized over the course of the study using the 
MMRM described in Section 6.4.1. The null hypothesis of no difference in the change from 
baseline between groups will be tested at each of the time points listed below. This analysis is 
part of the primary efficacy analysis and the individual test results will be obtained from the 
least squares means analysis for the primary efficacy analysis. The results will be presented in 
tabular form and line plots for each group over time. The endpoints, in the order to be tested, 
are as follows: 
 Change from baseline in the PEC score at 90 minutes 
 Change from baseline in the PEC score at 60 minutes 
 Change from baseline in the PEC score at 45 minutes 
 Change from baseline in the PEC score at 30 minutes 
 Change from baseline in the PEC score at 20 minutes 
  Change from baseline in the PEC score at 10 minutes 


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The fixed-sequence method will be used to adjust for multiplicity. 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. 
 
The estimand framework for this analysis is described in Table 4. 
 
Table 4.  Estimand attributes for the key secondary efficacy analysis 
 
Estimand attribute 
Description of attribute 
 
 
 
Target population 
ITT population – all patients who take any study medication 
and who had both baseline and at least one efficacy 
assessment after dosing 
Key secondary endpoints 
Absolute change from baseline in the total PEC total score at 
90, 60, 45, 30, 20, and 10 min 
Handling of intercurrent events 
All values collected after the use of rescue treatment and 
withdrawal from study will be set to missing. 
Population-level summary 
Difference between dose-specific treatment arm and placebo 
arm in mean change from baseline in the total PEC score using 
all measurements from baseline through 90, 60, 45, 30, 20, and 
 
10 minutes 
 
 
 
The trial product estimands are defined at each timepoint (90, 60, 45, 30, 20 and 10 minutes) as: 
• 
The difference in the mean change from baseline through the timepoint of analysis in 
the total PEC scores between the BXCL501 180µg arm and the placebo arm in the ITT 
population for subjects who did not use rescue medication. 
• 
The difference in the mean change from baseline through the timepoint of analysis in 
the total PEC scores between the BSCL501 120µg arm and the placebo arm in the ITT 
population for subjects who did not use rescue medication. 
 
6.4.3. 
Exploratory analyses 
 
The exploratory endpoints for this study and a description of the analysis approach for each 
endpoint are provided below: 
 Overall clinical improvement after drug administration as measured by the CGI-I 
score: This will be summarized for each timepoint with an ANCOVA, which will be 


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used to compare each of the dose groups to placebo at 30 minutes, 1 hour, 2 hours, 
and 4 hours. The model will include treatment group, study site, and age stratum as 
covariates. Empirical cumulative distribution function curves of the change in CGI-I 
will be presented for the change at each time point. The plots will include five curves 
representing the following five groups: ≥2 category decrease, 1 category decrease, no 
change, 1 category increase, and ≥2 category increase. An empirical cumulative 
distribution function curve of the change in CGI-I will also be presented for each 
treatment group versus placebo comparison and timepoint. 
  ACES scores at 2, 4, and 8 hours after dose administration: This will be evaluated 
using ANCOVA with baseline ACES, age stratum, study site, and treatment group as 
covariates at each timepoint. Empirical cumulative distribution function curves of 
the change in ACES will be presented for the change at each timepoint. The plots will 
include five curves representing the following seven groups: ≥3 category decrease, 
2 category decrease, 1 category decrease, no change, 1 category increase, 2 category 
increase, and ≥3 category increase. An empirical cumulative distribution function 
curve of the change in ACES will be presented for each treatment group versus 
placebo comparison and timepoint. 
  Change from baseline in total PEC score over time measured from 10 minutes 
through 24 hours after dosing: These results will be obtained from the MMRM used 
for the primary efficacy analysis with additional outcomes included in the model to 
include the 10-minute through 24-hour timeline. Empirical cumulative distribution 
function curves will also be presented for each treatment group versus placebo 
comparison and timepoint. Descriptive changes will also be summarized by study 
site. This will include the estimated mean change from baseline in total PEC score by 
time and treatment group for each study site to describe potential variation across 
sites. Forest plots will be constructed for important timepoints to summarize the 
results. 


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 PEC responders and CGI-I responders at 2 hours following dose of BXCL501 
compared with placebo: 
a. PEC responders will be defined as those who achieve at least a 
40% reduction in PEC total score from baseline at or before 2 hours 
post-dose and will be evaluated using a Fisher’s exact test for each dose 
group comparison. 
b. CGI-I responders will be defined as subjects with a score of 1 or 2 on the 
CGI-I scale (the CGI-I non-responders will be defined as subjects with 
scores from 3–7 at 2 hours) and will be evaluated using a Fisher’s exact 
test for each dose group comparison. 
 Time to rescue medication during the entire 24-hour post-treatment evaluation 
period for subjects receiving BXCL501 120µg or 180µg compared to placebo: 
Descriptive statistics will be used to evaluate this endpoint, with a Kaplan-Meier 
curve describing time to rescue medication estimated for each of the three groups 
(BXCL501 180µg, BXCL501 120µg, and placebo). A log rank test will be used to 
compare each of the two active treatment groups to placebo. 
 Number and proportion of subjects per treatment group who received rescue 
medication by 4 hours and within 24 hours after dosing: This will be evaluated using 
a Fisher’s exact test for each dose group comparison. 
  Duration of calming effect as described by the change from baseline in PEC total 
score, and ACES score at 2, 4, and 8 hours after dosing: This will be evaluated using 
the following definitions: 
For the PEC total score, calming is defined as achieving at least a 40% reduction 
in PEC score from baseline at or before 2 hours post-dose. 
For the ACES score, calming is defined as an improvement of 1 or more points in 
the ACES score relative to baseline. 
The proportion of subjects experiencing calmness at each timepoint will be described 
using plots and shift tables. 


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 Determine the safety profile of BXCL501 as measured by vital signs and 
treatment-emergent AE reports: Descriptive methods including frequency 
distributions, box plots, shift tables and listings will be used to present the safety 
data. All safety data will be presented by treatment group. 
 Describe the overall tolerability in terms of AE reports and local site (oral/sublingual) 
tolerability of oral film: Descriptive methods, including frequency distributions and 
listings, will be used to describe tolerability. 
 Descriptive PK of BXCL501 120µg and 180µg in the patient population: This will be 
presented in a separate PK report. Tables of PK parameters will be presented. 
 Determine patient acceptability, taste and likability of study medication using Likert 
scales to capture subject’s acceptability, opinion on taste, and questions regarding 
likability: An ANCOVA will be used to describe any differences between the 
BXCL501 dose groups and placebo groups. 
 Characterize the patient population utilizing the YMRS: Two-sample t-tests will be 
used to describe any differences between the BXCL501 and placebo groups in the 
change from baseline in YMRS. 
 
An additional exploratory efficacy endpoint, time to resolution of agitation as measured by 
achieving an ACES score of at least 4, will also be analyzed. A Fisher’s exact test for difference 
in proportions of subjects with resolution will be conducted at each timepoint for each dose 
group comparison. The results will be presented in tabular form and graphically. 
 
7. 
Safety analyses 
 
All safety analyses will be performed using the safety population. Safety and tolerability will 
be assessed by clinical review of all safety parameters including AEs, laboratory values, and 
vital signs. The safety analyses will include all results collected from randomization through 
the end of the study. All safety presentations will be presented by treatment group (BXCL501 
180µg, BXCL501 120µg, and placebo). 


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7.1. 
Adverse events 
 
AEs will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA) version 22.0 
coding system. Frequency tables will be presented by treatment groups summarizing: 
• 
All treatment-emergent AEs 
• 
All treatment-emergent AEs by severity 
• 
All treatment-emergent treatment-related AEs 
• 
All serious treatment-emergent AEs 
• 
All AEs leading to discontinuation 
 
7.2. 
Clinical laboratory evaluations 
 
Each laboratory value and change from baseline (when appropriate) will be summarized in 
tables and figures for hematology, blood chemistry and urinalysis for each treatment at 
Screening, discharge, and end of study. Boxplots of laboratory values will be provided. 
 
7.3. 
Physical examination 
 
A listing of physical examination findings will be provided by subject. 
 
7.4. 
Vital signs 
 
Each resting vital sign observed value and change from baseline (when appropriate) will be 
summarized for each treatment group at Screening, pre-dose, 30 minutes, 1 hour, 2 hours, 
4 hours, 6 hours, 8 hours, and 24 hours post–dose administration. Each orthostatic vital sign 
observed value and change from baseline (when appropriate) will be summarized for each 
treatment group at Screening, pre-dose, 2 hours, 4 hours, 8 hours, and 24 hours post–dose 
administration. 
 
7.5. 
12-lead electrocardiogram 
 
Each 12-lead ECG observed value and change from baseline (when appropriate) will be 
summarized for each treatment group at Screening, pre-dose (not required if Screening ECG is 
conducted on the day of dosing), 2 hours, and 24 hours post–dose administration. In addition, 
frequency tabulation of the overall ECG results (Normal, abnormal normalized cumulative 


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sum [NCS], and abnormal cumulative sum [CS]) will be summarized (to include any emergent 
arrhythmias and determination of resolution). Conduction intervals including PR, QRS, QT 
(>450, >500ms) and QTc (>450, >500 ms) will be summarized and tabulated. Shift tables of 
clinically significant findings will be reported for corresponding QT and QTc interval changes. 
 
7.6. 
Concomitant medications 
 
Concomitant medications will be summarized (n and %) by anatomical therapeutic chemical 
(ATC) class and preferred term (coded by WHO Drug coding dictionary March 2019) for each 
treatment group. This table will also include an overall total column. 
 
7.7. 
Buccal exam for local irritation 
 
The local irritation will be assessed by buccal exam at 30 minutes, 2 hours, 4 hours, and 
24 hours post-dose based on following parameters: 
• 
Negative reaction to the sub-lingual film in the examiner’s opinion (Yes/No): 
assessed at all above time points. 
• 
Time taken for medication to dissolve (1–30 seconds, 31–59 seconds, 1–2 minutes, 
3+ minutes): only assessed at 30 minutes. 
 
A frequency summary and figure will be presented for these parameters for each treatment 
group at each timepoint. 
 
8. 
References 
 
1. 
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: First MB, ed. Standardized Evaluation in Clinical Practice. Washington, DC: 
American Psychiatric Publishing, 103–131, 2003. 


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9. 
Appendix 
 
This appendix contains details for programming the MMRM and the techniques to be applied 
to account for missing data. This code is pseudocode and will need to be tested on a blinded 
data transfer before being finalized. The code presented here will be finalized before the final 
database lock as part of the programming specifications. 
 
9.1. 
MMRM analysis 
 
Table 5 contains pseudo SAS code with the variables defined as follows: 
• 
DOSE – treatment group assignment with dose of 120µg and 180µg 
• 
VISITNUM – denotes time of measurement (10, 20, 30, 45, 60, 90, and 120 minutes) 
• 
AGE_STRATA – indicates age stratum for randomization 
• 
SITE – study site 
• 
CHG_PEC – change from baseline in PEC total score 
• 
VISITNUM*DOSE – interaction of visit and dose group 
• 
BASE_PEC*VISITNUM – interaction of visit and baseline PEC measure 
 
The LSMEANS statement will be provide information on all possible differences for 
VISITNUM*DOSE. The ESTIMATE statements provide information for the specific 
comparison and should be checked against the LSMEANS output to ensure that the correct 
values were extracted. 
 
The code in Table 5 will be used for all of the MMRM analyses proposed in this SAP with 
appropriate modifications made for the variable names and number of repeated measures. 


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Table 5. SAS code for MMRM analysis 
 
proc mixed data=OUT2 method=reml alpha=0.025 covtest; 
class VISITNUM(ref=LAST) 
DOSE(ref = “0”) PATNO AGE_STRATA SITE; 
model CHG_PEC = BASE_PEC AGE_STRTA SITE DOSE VISITNUM 
VISITNUM*DOSE BASE_PEC*VISITNUM 
/ solution ddfm=kr; 
repeated VISITNUM / subject=PATNO type=un r; 
lsmeans VISITNUM*DOSE / diff om cl e; 
estimate ‘180 - PBO at 120 minutes’ DOSE 0 1 -1 
VISITNUM*TRTGRP 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 -1 
/ CL; 
estimate ‘120 - PBO at 120 minutes’ DOSE 1 0 -1 
VISITNUM*TRTGRP 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 -1 
/ CL; 
ods output estimates=SI_ESTIMATES; 
  run; 
 
 
 
 
9.2. 
Methods for missing data 
 
Missing data is less of an issue in this trial due to the in-clinic nature of the data collection; 
however, this SAP prespecifies the use of multiple imputation to account for the potential for 
missing data. Multiple imputation will be performed based on missing at random multiple 
imputation, in which imputed values are based on the treatment group to which the subject is 
randomized, and on control-based imputation, in which imputed values are obtained from the 
placebo group rather than the treatment group to which the subject is randomized. The 
imputation process will assume that the data are monotone missing with 100 imputed datasets 
derived for each of the two scenarios. All results of this sensitivity analysis will be 
summarized in tables and a forest plot. 
 
The first step in the imputation process consists of the steps outlined below: 
 Use multiple imputation to create 100 datasets that satisfy the assumption of 
monotone missingness (see Table 6). 
 Using the datasets from step 1, use multiple imputation to create 100 complete 
datasets (see Table 7 for code for missing at random imputation and Table 10 for 
code for control-based imputation). 
  Fit the MMRM model to each of the 100 complete datasets (see Table 8). 


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  Use Rubin’s rule (PROC MIANALYZE) to obtain the combined estimates and final 
result (see Table 9). 
 
Table 6. SAS code to create datasets satisfying monotone missing condition 
 
proc sort data= DATA_IMP(observed data set); 
by PATNO DOSE AGE_STRAT SITE BASE_PEC; 
run; 
 
proc transpose data= DATA_IMP out=DATA_IMP; 
by PATNO DOSE AGE_STRAT SITE BASE_PEC; 
ID VISITNUM; 
VAR CHG_PEC; 
run; 
 
proc sort data= DATA_IMP; 
by PATNO; 
run; 
 
proc mi data=DATA_IMP nimpute=100 round=0.1 seed= 
out=OUT_IMP_CONT_DOSE0; 
where DOSE=’O’; 
var 
 BASE_PEC(baseline) AGE_STRAT SITE 
DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min); 
mcmc chain=multiple impute=monotone; 
run; 
 
proc mi data=DATA_IMP nimpute=100 round=0.1 seed= 
out=OUT_IMP_CONT_DOSE120; 
where DOSE=’120’; 
var 
 BASE_PEC(baseline) AGE_STRAT SITE 
DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min); 
mcmc chain=multiple impute=monotone; 
 run; 
 
(page 1 of 2) 


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Table 6. SAS code to create datasets satisfying monotone missing condition, continued 
 
proc mi data=DATA_IMP nimpute=100 round=0.1 seed= 
out=OUT_IMP_CONT_DOSE180; 
where DOSE=’180’; 
var 
 BASE_PEC(baseline) AGE_STRAT SITE 
DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min); 
mcmc chain=multiple impute=monotone; 
run; 
 
data OUT_IMP_CONT; 
set OUT_IMP_CONT_DOSE0 OUT_IMP_CONT_DOSE120 
OUT_IMP_CONT_DOSE180; 
 run; 
 
(page 2 of 2) 
 
The 100 datasets satisfying the condition of monotone missingness will be contained in the 
dataset OUT_IMP_CONT. The next step in the process is to fill in any remaining values using 
multiple imputation. 
 
9.2.1. 
Missing at random imputation 
 
The code presented in Table 7 will fill in any remaining missing values using missing at 
random imputation, where subjects’ data are imputed based on the treatment group to which 
they were randomized. 


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Table 7. SAS code for missing at random imputation 
 
proc sort data= DATA_IMP_CONT; 
by PATNO; 
run; 
 
proc mi data=OUT_IMP_CONT (where= (DOSE=”0”)) nimpute=1 round=0.1 
seed= out=IMPDAT_DOSE0; 
by _IMPUTATION_; 
class AGE_STRAT SITE; 
var 
 BASE_PEC(baseline) AGE_STRAT SITE 
DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min); 
monotone reg (DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min)/details); 
run; 
 
proc mi data=OUT_IMP_CONT (where= (DOSE=”120”)) nimpute=1 round=0.1 
seed= out=IMPDAT_DOSE120; 
by _IMPUTATION_; 
class AGE_STRAT SITE; 
var 
 BASE_PEC(baseline) AGE_STRAT SITE 
DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min); 
monotone reg (DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min)/details); 
run; 
 
proc mi data=OUT_IMP_CONT (where= (DOSE=”180”)) nimpute=1 round=0.1 
seed= out=IMPDAT_DOSE180; 
by _IMPUTATION_; 
class AGE_STRAT SITE; 
var 
 BASE_PEC(baseline) AGE_STRAT SITE 
DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min); 
monotone reg (DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min)details); 
 run; 
 
(page 1 of 2) 


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Table 7. SAS code for missing at random imputation, continued 
 
data RANDOM_IMP; 
set IMPDAT_DOSE0 IMPDAT_DOSE120 IMPDAT_DOSE180; 
run; 
 
(page 2 of 2) 
 
The output dataset is then used for the analysis. This dataset must be transposed for the 
MMRM analysis. For the SAS code in Table 8, it is assumed that the dataset COMBINE 
includes the 100 datasets. 
 
Table 8. SAS code for MMRM analysis as part of the imputation process 
 
proc mixed data=COMBINE method=reml alpha=0.025 covtest; 
by _IMPUTATION_; 
class VISITNUM(ref=LAST) DOSE PATNO AGE_STRAT SITE; 
model DELT_PEC = BASE_PEC AGE_STRAT DOSE SITE 
VISITNUM VISITNUM*DOSE BASE_PEC*VISITNUM 
/ solution ddfm=kr; 
repeated VISITNUM / subject=PATNO type=un r; 
estimate ‘180 - PBO at 120 minutes’ DOSE 0 1 -1 
VISITNUM*TRTGRP 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 -1 
/ CL; 
estimate ‘120 - PBO at 120 minutes’ DOSE 1 0 -1 
VISITNUM*TRTGRP 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 -1 
/ CL; 
ods output estimates=SI_ESTIMATES; 
run; 
 
 
 
This analysis will produce 100 estimates of the difference between the dose group of interest 
(BXCL501 180µg or BXCL501 120µg) and placebo in change from baseline in PEC at 
120 minutes. These values are contained in SI_ESTIMATES. Table 9 provides the code for the 
implementation of Rubin’s rules to obtain the combined estimates of treatment effect at the 
two dose levels. 
 
Table 9. SAS code for Rubin’s rule 
 
proc mianalyze data=LSM alpha=0.025; 
by TRT VISITNUM; 
modeleffects estimate; 
stderr stderr; 
ods output ParameterEstimates=Week_48_MMRM_LSM; 
run; 
 


CONFIDENTIAL 
 
BXCL501-302 STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 35 
 
 
9.2.2. 
Control-based imputation 
 
The second part of the sensitivity analysis includes multiple imputation where all missing data 
values are imputed as if the subject were in the placebo group. The steps are the same as those 
for the standard imputation outlined above, but the code provided in Table 7 is replaced with 
the code in Table 10. The input dataset for this analysis is OUT_IMP_CONT, which is the 
dataset that satisfies the condition of monotone missingness and is created from the code 
provided in Table 10. 
 
Table 10. SAS code for control-based imputation 
 
proc sort data= OUT_IMP_CONT; 
by _IMPUTATION_ PATNO; 
run; 
 
proc mi data=OUT_IMP_CONT nimpute=1 round=0.1 seed= 
out=CONT_BASED_CONTROL; 
by _IMPUTATION_; 
class AGE_STRAT DOSE SITE; 
var 
 BASE_PEC(baseline) AGE_STRAT SITE 
DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min); 
 
mnar model(DELT_PEC10(10 min) DELT_PEC20(20 min) 
DELT_PEC30(30 min) DELT_PEC45(45 min) 
DELT_PEC60(60 min) DELT_PEC90(90 min) 
DELT_PEC120(120 min); 
/ modelobs=(DOSE='0')); 
 run; 
 
 
The output dataset CONT_BASED_CONTROL must be transposed, then the code provided in 
Table 8 and Table 9 is used to obtain the final result. 
 
E:\Proj\Bioxcel\2. SAP\Phase 3 SAP\bipolar\BXCL501-302 SAP v10.docx\AD 


BioXcel Therapeutics, Inc. 
Protocol BXCL501-302 
Statistical analysis plan addendum 
This addendum to the BioXcel Therapeutics, Inc. BioXcel protocol BXCL501-302 statistical 
analysis plan (SAP), dated April 1, 2020, describes the following changes to be made to the 
SAP: 
• 
To ensure consistency with the availability of assessments per the schedule of events, 
nominal timepoints, rather than protocol-specified time windows as specified in 
Section 6.1.3 of the SAP, will be used to determine the timepoint assigned to each 
observation. 
• 
Exploratory endpoints that were specified to be assessed using ANOVA or 
ANCOVA and are available at multiple timepoints will instead use the MMRM 
approach specified for the primary analysis, using baseline as a covariate if a 
baseline assessment is available for that measure. These include CGI-I (using CGI-S 
as a baseline covariate, with a dependent variable of CGI-I – not change) and ACES 
(with a dependent variable of change from baseline). 
• 
As a point of clarification, the exploratory endpoint of PEC response by 2 hours 
(Section 4.3.3, 4.a.) will include all subjects who meet the definition of response (i.e., 
:'. 40% reduction from baseline) on or before 2 hours, irrespective of whether or not 
that reduction is maintained until the 2-hour timepoint. 
• 
Graphical displays may be revised from what is specified in the SAP based on a 
detailed review of proposed TLFs. 
 
 
 
 
Lisa Weissfeld, PhD 
Senior Investigator, Statistics Collaborative, Inc. 
Date: 
May 20, 2020 
 
 
 
 
May 20, 2020 
 
Robert Risinger, MD 
VP, Clinical Deveopment, BioXcel Therapeutics, Inc. 
Date: 
 
 
 
E:\Proj\Bioxcel\2. SAP\Phase 3 SAP\bipolar\BXCL501-302 SAP addendum v03.docx\AD 


BioXcel Therapeutics, Inc. 
Protocol BXCL501-302 
Statistical analysis plan addendum 
This addendum to the BioXcel Therapeutics, Inc. Protocol BXCL501-302 statistical analysis 
plan (SAP) dated June 8, 2020, describes the following changes to be made to address concerns 
that FDA raised concerning the clarity of the estimands and the handling of intercurrent 
events. Their specific concern is as follows: 
“Your description of the primary estimand is not clear. You did not provide a 
rationale either, so it is difficult for us to evaluate it. Is the use of rescue treatment the 
only relevant intercurrent event needing to handle? You need to first list all 
intercurrent events, then clarify the strategy for handling each listed intercurrent 
event with rationale. For instance, what is the rationale for excluding from the 
primary analysis model the observations collected while on rescue medication (that 
is, considering the values missing)? Also, please provide the anticipated percentage 
of patients who may need rescue medication during the two hours. You should plan 
a sensitivity analysis by including all observations whether on rescue medication or 
not.” 
 
The primary estimands are defined as: 
• 
The difference in the mean change from baseline through 120 minutes in the total 
PEC scores between the BXCL501 180µg arm and the placebo arm in the ITT 
population for subjects who did not use rescue medication 
• 
The difference in the mean change from baseline through 120 minutes in the total 
PEC scores between the BXCL501 120µg arm and the placebo arm in the ITT 
population for subjects who did not use rescue medication 
 
The two intercurrent events are the use of rescue medication and withdrawal from study. 
Given the short treatment period of 120 minutes and the fact that rescue medication was not 
allowed during this time interval, we anticipated that there would be few intercurrent events. 
This thinking was further supported by the results of the phase 2 study (BXCL501-102) where 
there were no missing data in the first 120 minutes and no rescue medication in the first 


BXCL501-302 STATISTICAL ANALYSIS PLAN ADDENDUM 2 
June 8, 2020 
Page 2 
 
 
120 minutes in the cohorts where it was prohibited. The SAP should have provided this 
information to clarify our thinking around the handling of intercurrent events. 
 
As both the BXCL501-301 and -302 studies are now complete, we can confirm that there was 
no use of rescue medication in the first 120 minutes, and there are no missing values in this 
time interval. The SAP provides details on methods for missing data if missing data had been 
a problem. 
 
Considering this information, the section describing the estimands is changed as follows: 
 
6.4 Efficacy analyses 
 
The efficacy analysis will be conducted within the estimand framework. A summary of the 
attributes of the estimand is provided in Table 1. 
 
Table 1. 
Estimand attributes for the primary efficacy analysis 
 
Estimand attribute 
Description of attribute 
 
 
 
Target population 
ITT population—All patients who take any study medication 
and who had both baseline and at least one efficacy 
assessment after dosing 
Primary endpoint 
Absolute change from baseline in the total PEC total score at 
120 minutes 
Handling of intercurrent events 
No intercurrent events, including missing values or use of 
rescue treatment, were observed from baseline through 
120 minutes 
Population-level summary 
Difference between dose-specific treatment arm and placebo 
arm in mean change from baseline in the total PEC score using 
 
all measurements from baseline through 120 minutes 
 
 
 
The trial product estimands are defined as: 
• 
The difference in the mean change from baseline through 120 minutes in the total 
PEC scores between the BXCL501 180µg arm and the placebo arm in the ITT 
population 
• 
The difference in the mean change from baseline through 120 minutes in the total 
PEC scores between the BXCL501 120µg arm and the placebo arm in the ITT 
population 


BXCL501-302 STATISTICAL ANALYSIS PLAN ADDENDUM 2 
June 8, 2020 
Page 3 
 
 
The null and alternative hypotheses to be tested for these estimands are H01: ∆BXCL501_180 = ∆PBO, 
HA1: ∆BXCL501_180 ≠ ∆PBO, H02: ∆BXCL501_120 = ∆PBO, and HA2: ∆BXCL501_120 ≠ ∆PBO, where ∆BXCL501_180 
denotes the change from baseline in the PEC score at 2 hours post-dose in the BXCL501 180µg 
group, ∆BXCL501_120 denotes the change from baseline in the PEC score at 2 hours post-dose in 
the BXCL501 120µg group, and ∆PBO denotes the change from baseline in the PEC at 2 hours 
post-dose in the placebo group. The null hypotheses, H01 and H02, 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 
and set at 0.025. For the analysis of the key secondary endpoints, a Bonferroni correction will 
be applied, and each hypothesis will be tested using a significance level of 0.025. A fixed 
sequence approach will then be used to adjust for the multiple testing at each timepoint. 
 
 
 
 
Date: 
June 8, 2020 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
E:\Proj\Bioxcel\2. SAP\Phase 3 SAP\bipolar\BXCL501-302 SAP addendum 2 v03.docx\AD 


BioXcel Therapeutics, Inc. 
Protocol BXCL501-302 
Statistical analysis plan addendum 
This addendum to the BioXcel Therapeutics, Inc. Protocol BXCLS0l-302 statistical analysis 
plan (SAP) dated July 7, 2020, describes the following change to be made to the analysis 
involving the Young Mania Rating Scale. 
 
The SAP currently reads as follows: 
1. Characterize the patient population utilizing the YMRS: Two-sample t-tests will be 
used to describe any differences between the BXCL501 and placebo groups in the 
change from baseline in YMRS. 
 
And will be changed to read: 
1. Characterize the patient population utilizing the YMRS: An ANCOVA model will be 
used to describe any differences between the BXCL501 and placebo groups in the 
change from baseline in YMRS and will include the baseline value of the YMRS as a 
covariate. 
 
As an additional note, one subject is missing a single PEC value during the primary outcome 
window of two hours. All other subjects have complete data. 
 
 
Date: 
07JUL2020 
 
 
 
7/7/2020 
Date: 
 
 
 
 
 
E:\Proj\Bioxcel\2. SAP\Phase 3 SAP\bipolar\BXCL501-302 SAPaddendum 3 v01.docx\LW 


BioXcel Therapeutics, Inc. 
Protocol BXCL501-302 
Statistical analysis plan addendum to evaluate 
clinically ·meaningful change 
 
This addendum to the BioXcel Therapeutics, Inc. Protocol BXCLS0l-3O2 statistical analysis 
plan (SAP) dated January 20, 2021, includes additional analyses to address clinically meaningful within 
patient change in PEC scores using anchor-based methods and cumulative distribution function curves. 
The following analyses will be conducted: 
 
 
1. An analysis of covariance (ANCOVA) will beperfor_med (PROC GLM) using the CGl-1 rating at 2 
hours post administration controlling for age, sex and baseline PEC Score. The individual 
response options of the CGl-1 will be used as individual groups to examine the PEC change score 
but may also be collapsed pending sample size of each response group. 
 
2. Empirical cumulative distribution function (eCDF) curves will be programmed to evaluate the 
raw change score of the PEC at 2 hours post-dose on the ITT population as follows: 
a. By treatment group assignment 
b. By CGl-lmprovement rating 
 
3. Probability density function (PDF) plots will be programmed to evaluate the raw change score of 
the PEC at 2 hours post-dose on the ITT population as follows: 
a. By treatment group assignment 
b. By CGl-lmprovement rating 
 
4. Mean change score and effect sizes will be calculated for the overall sample, by treatment 
assignment, and by CGI-improvement group to provide distribution-based support for the above 
analyses. 
 
 
 
 
 
 
 
Date: