Characterization of Tachyphylaxis, Tolerance, and Withdrawal After Discontinuation of Igalmi in Frequently Agitated Schizophrenic or Bipolar Patients After 7 Days of PRN Treatment
Phase: PHASE4
Conditions: Bipolar Disorder, Schizophrenia, Agitation,Psychomotor, Schizo Affective Disorder, Schizophreniform Disorders
Sponsor: BioXcel Therapeutics Inc

 
 CHARACTERIZATION OF TACHYPHYLAXIS, TOLERANCE, AND WITHDRAWAL AFTER 
DISCONTINUATION OF IGALMI IN FREQUENTLY AGITATED SCHIZOPHRENIC OR BIPOLAR 
PATIENTS AFTER 7 DAYS OF PRN TREATMENT 
 
NCT06041646 
 
October 26, 2023 

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CHARACTERIZATION OF TACHYPHYLAXIS, TOLERANCE, AND WITHDRAWAL
AFTER DISCONTINUATION OF IGALMI IN FREQUENTLY AGITATED 
SCHIZOPHRENIC OR BIPOLAR PATIENTS AFTER 7 DAYS OF PRN TREATMENT  
 
 
PROTOCOL NUMBER: 
BXCL501-404 
STUDY PHASE: 
Phase 4 
 
IND NUMBER:
140184 
PROTOCOL VERSION:
Version 6.0 
 
PROTOCOL DATE: 
AMENDMENT 1: 
AMENDMENT 2:     
AMENDMENT 3:
AMENDMENT 4:
AMENDMENT 5:                   
16DEC2022 
09MAR2023
18MAY2023 
06JUN2023 
10AUG2023 
26OCT2023 
SPONSORED BY:
BioXcel Therapeutics, Inc. 
555 Long Wharf Drive 
12th Floor  
New Haven, CT 06511 
Phone: 
 
 
 
 
 
 
This study will be performed in compliance with Good Clinical Practices and applicable regulatory requirements, 
including the archiving of essential documents. Information contained in this protocol is confidential in nature, and 
may not be used, divulged, published or otherwise disclosed to others except to the extent necessary to obtain 
approval of the Institutional Review Board or Independent Ethics Committee, or as required by law. Persons to 
whom this information is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of BioXcel Therapeutics, Inc. 

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2.
INVESTIGATOR AGREEMENT
PROTOCOL TITLE:  
CHARACTERIZATION OF TACHYPHYLAXIS, TOLERANCE, 
AND WITHDRAWAL AFTER DISCONTINUATION OF 
IGALMI IN FREQUENTLY AGITATED SCHIZOPHRENIC OR 
BIPOLAR PATIENTS AFTER 7 DAYS OF PRN TREATMENT  
PROTOCOL NUMBER:  
BXCL501-404 
 
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., Lotus Clinical Research, LLC, 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  
Activity 
*Screening  
(Within 15 days 
of first dose) 
Days 1 – 7 PRN Dosing (Per 
Episode) 
 
Follow Up/Early 
Termination11 
Time point 
 
Pre-Dose  
2 hrs Post-Dose 
(+/- 30 mins) 
 
Days 8 – 10 
Informed consent 
X 
 
 
 
Medical history
X
Inclusion/Exclusion criteria 
X 
X 
 
 
Demographics
X
Height  
X 
 
 
 
Weight and BMI 
X 
 
 
 
Physical exam 
X 
 
 
 
Neurological exam 
X 
 
 
 
Safety laboratory 
assessments  
X1 
 
 
 
Urine Pregnancy Test 
(females of childbearing 
potential) 
X 
 
X2 
 
 
UDS and Breathalyzer 
X1 
X2 
 
 
Resting vital signs  
X 
X3 
X 
X3 
Orthostatic vital signs9, 10 
X 
X3 
X 
X3 
Heart Rate 
X 
X3 
X 
X3 
ECG 
X 
 
X4 
X5 
Trial drug administration  
 
X 
 
 
PEC 
 
X6 
X 
X7 
CGI-S 
 
X 
 
 
CGI-I 
 
 
X 
 
ACES 
 
X8 
X 
 
C-SSRS 
X 
 
 
 
Concomitant medications  
X 
X 
X 
X 
Adverse events  
X 
X 
X 
X 
Notes to the Pre-First-and Post-Dose Schedule of Events: 
*Screening (Within 15 days of first dose): if no agitation episode occurs within 15 days subject can be re-screened 
only once. If after the re-screen, another 15 days has passed without a dosing episode, then the patient will be 
deemed a screen fail. If re-screen occurs greater than 30 days from Screening visit, all Screening assessments must 
be completed. If less than 30 days, re-screen assessments will be completed on a case-by-case basis with PI and 
Sponsor discretion.

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1 Safety labs and UDS results must be available prior to dosing. 
2Urine Pregnancy Test, UDS and Breathalyzer conducted on Day 1 pre-dose first agitation episode only. 
3 Resting vital signs, orthostatic vital signs, and heart rate will be taken prior to agitation episodes if possible. Even 
if subject does not have an agitation episode during Follow Up/Early Termination, resting vital signs, orthostatic 
vital signs, and heart rate must be collected daily during this period.
4 ECG to be performed 2 hours post first dose only on Day1.  
5 ECG to be performed during follow up/Early Termination period regardless if subject had an agitation episode. If 
subject was dosed on Day 7 ECG should be collected at least 24 hours post their last dose on Day 7.    
6 PEC will be conducted within 15 minutes of dosing. 
7 PEC ratings during 3 day Follow Up/ Days 8 – 10/ Early Termination will be collected before and after dosing 
with the subjects’ standard of care medication at the time of an agitation episode.  
8 ACES will be conducted within 15 minutes prior to  dosing. 
9 Temperature and respiratory rate will be recorded at the time of “resting” (i.e.: supine) vital signs measurement 
and are not required to be measured at each of the subsequent “orthostatic” (i.e.: sitting / standing) vital sign 
timepoints. 
10 “Orthostatic” vitals are the values obtained for blood pressure and heart rate with the patient in the sitting / 
standing position. “Resting” vitals are the values obtained for all vital signs (blood pressure, heart rate, temperature, 
and respiratory rate) with the patient in the supine position. 
11  Follow-Up / Early Termination period will follow the same time window (both pre- and post-dose) as days 1-7.  
 
 

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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 ............................................................................ 14
4.1. 
List of Tables ..............................................................................................................17
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......... 18
6. 
INTRODUCTION ....................................................................................... 20
6.1.
Background and Rationale .......................................................................................20
6.2.
Description ..................................................................................................................21
7. 
OBJECTIVES AND ENDPOINTS ............................................................ 22
7.1. 
Primary Objective ......................................................................................................22
7.1.1.
Endpoints in support of Primary Objective ......................................................22
7.2. 
Secondary Objective ..................................................................................................22
7.2.1.
Endpoints in support of Secondary Objective ..................................................22
8. 
STUDY DESIGN ......................................................................................... 23
8.1. 
Overall Study Design and Plan .................................................................................23
8.2. 
Study Sites...................................................................................................................23
9. 
SUBJECT POPULATION .......................................................................... 24
9.1. 
Inclusion Criteria .......................................................................................................24
9.2. 
Exclusion Criteria ......................................................................................................24
9.3. 
Removal of Subjects from Therapy or Assessment ................................................25
10. 
STUDY TREATMENTS ............................................................................. 26
10.1. 
Method of Assigning Subjects to Treatment Groups .............................................26
10.2. 
Identification of Investigational Product .................................................................26
10.3. 
Treatment Administration ........................................................................................26
10.4. 
Storage ........................................................................................................................26
10.5. 
Labeling ......................................................................................................................26
10.6. 
Drug Accountability...................................................................................................26
10.7. 
Treatment Compliance ..............................................................................................27
10.8. 
Concomitant Medications .........................................................................................27

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10.9. 
Permitted Therapies ..................................................................................................27
10.9.1. 
Rescue Medication ...............................................................................................27
10.9.2. 
Prohibited Therapies ...........................................................................................27
11. 
STUDY PROCEDURES ............................................................................. 28
11.1. 
Screening .....................................................................................................................28
11.2. 
Days 1 – 7, Pre-Dose ...................................................................................................28
11.3. 
Days 1 – 7, Post-Dose Assessments ...........................................................................29
11.4. 
Days 8 – 10, Follow Up/Early Termination .............................................................29
12.
STUDY ASSESSMENTS............................................................................31
12.1. 
Efficacy........................................................................................................................31
12.1.1. 
PANSS – Excitatory Component (PEC) ............................................................31
12.1.2. 
Clinical Global Impressions-Improvement (CGI-I) .........................................31
12.1.3. 
Clinical Global Impression-Severity (CGI-S) ...................................................31
12.2. 
Safety ...........................................................................................................................32
12.2.1. 
Adverse Events .....................................................................................................32
12.2.1.1.
Adverse Event Definitions .............................................................................32
12.2.1.2.
Eliciting and Documenting Adverse Events ................................................33
12.2.1.3.
Reporting Adverse Events .............................................................................33
12.2.1.4.
Follow-up of Adverse Events ........................................................................35
12.2.2. 
C-SSRS ..................................................................................................................35
12.2.3. 
Laboratory Safety Assessments ..........................................................................35
12.2.4. 
Vital Signs .............................................................................................................36
12.2.5. 
ACES .....................................................................................................................36
12.2.6. 
Electrocardiogram ...............................................................................................37
12.2.7. 
Physical Examination ..........................................................................................37
12.2.8. 
Concomitant Medications ...................................................................................37
13. 
STATISTICAL METHODS ....................................................................... 38
13.1. 
General Considerations .............................................................................................38
13.2. 
Analysis Populations ..................................................................................................38
13.3. 
Statistical Analyses.....................................................................................................38
13.3.1. 
Subject Disposition and Demographic Characteristics ....................................38
13.3.2. 
Tachyphylaxis and Withdrawal Analyses .........................................................38

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13.3.3. 
Safety Analyses .....................................................................................................39
13.4. 
Sample Size Determination .......................................................................................40
14. 
STUDY CONDUCT .................................................................................... 41
14.1. 
Sponsor and Investigator Responsibilities ...............................................................41
14.1.1. 
Sponsor Responsibilities ......................................................................................41
14.1.2. 
Investigator Responsibilities ...............................................................................41
14.2. 
Site Initiation ..............................................................................................................41
14.3. 
Study Documents .......................................................................................................42
14.3.1. 
Good Clinical Practice Documents .....................................................................42
14.3.2. 
Case Report Forms ..............................................................................................42
14.3.3. 
Source Documents ................................................................................................43
14.4. 
Data Quality Control .................................................................................................43
14.4.1. 
Monitoring Procedures ........................................................................................43
14.4.2. 
Data Management ................................................................................................44
14.4.3. 
Quality Assurance/Audit .....................................................................................44
14.5. 
Study Termination .....................................................................................................44
14.5.1. 
Regular Study Termination ................................................................................44
14.5.2. 
Premature Study Termination............................................................................44
14.6. 
Study Site Closure ......................................................................................................45
14.6.1. 
Record Retention .................................................................................................45
14.6.2. 
Sample Retention .................................................................................................45
14.7. 
Changes to the Protocol .............................................................................................46
14.8. 
Use of Information .....................................................................................................46
15. 
FINAL CLINICAL STUDY REPORT ..................................................... 47
16. 
ETHICAL AND LEGAL CONSIDERATIONS ...................................... 48
16.1. 
Declaration of Helsinki and Good Clinical Practice ...............................................48
16.2. 
Subject Information and Informed Consent ...........................................................48
16.3. 
Approval by Institutional Review Board .................................................................48
17. 
REFERENCES ............................................................................................ 49

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4.1.
List of Tables
Table 1.1: Sponsor/CRO Contact Information ..........................................................................3
Table 3.1: Schedule of Events ....................................................................................................12

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5.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse event
ACES 
Agitation-Calmness Evaluation Scale 
BID
Twice daily
BP 
Blood pressure
BMI 
Body Mass Index 
C 
Celsius/Centigrade 
CGI-I
Clinical Global Impression-Improvement
CGI-S
Clinical Global Impression-Severity
CNS 
Central nervous system
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale
CV 
Cardiovascular 
DBP 
Diastolic blood pressure 
Dex or DEX 
Dexmedetomidine
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
ET 
Early Termination 
FDA 
US Food and Drug Administration 
FD&C 
United States Federal Food, Drug, and Cosmetic Act
g 
gram
GCP 
Good Clinical Practices 
HR 
Heart rate 
hr 
hour
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IM 
Intramuscular 

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Abbreviation 
Definition 
IP 
Intraperitoneal 
IRB 
Institutional Review Board
IUD 
Intrauterine Device 
IV  
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg
milligram 
MHRA
Medicines and Healthcare products Regulatory Agency
Min 
Minutes 
mm 
millimeters
mmHg 
millimeters of mercury 
µg 
microgram 
n  
Number
PEC 
Positive and Negative Syndrome Scale – Excited Component 
pH 
Measure of hydrogen ion concentration
PI 
Principal Investigator 
po 
oral/by mouth 
PRN 
As needed 
RR 
Response Rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SL 
Sublingual 
SOC 
Standard of care 
TEAE 
Treatment emergent adverse event 
THC 
Tetrahydrocannabinol 
UDS 
Urine Drug Screen 
US
United States of America

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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 (Porsteinsson and  Antonsdottir 
2017), 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).   
IGALMI is currently approved in the US as the sublingual formulation, Igalmi® (BioXcel US 
Package Insert 2022), for the acute treatment of agitation associated with schizophrenia and 
bipolar I and II disorders.  Dexmedetomidine is also 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 
by direct absorption into the blood through the oral mucosal route and no route-specific safety 
signals (oral mucosal or gastrointestinal). IGALMI is designed as a self-administered discrete 
low dose film with mucoadhesive properties.  
Clinical Experience 
IGALMI has been evaluated in multiple completed clinical trials in healthy volunteers and in 
agitated patients with schizophrenia or bipolar I or II disorder or dementia and for the mitigation 
of withdrawal symptoms following abrupt discontinuation of opioids. In these trials, more than 
800 subjects have received doses of 10 µg to 480 µg /day. The Phase 3 clinical trials (BXCL501-
301 and BXCL501-302) demonstrated that a single sublingual dose of IGALMI at 180 µg or 120 
µg effectively and rapidly reduced the severity of an acute agitation episode in subjects with 
schizophrenia or schizoaffective disorder and subjects with bipolar disorder. The safety data 
collected in this trial showed that IGALMI 
and had a favorable safety profile in the treatment of subjects with agitation. The TEAEs 
reported in this trial were consistent with known common side effects of dexmedetomidine, 
namely dry mouth, bradycardia, hypotension, and somnolence.  
Additionally, there are ongoing trials for IGALMI), including a trial in children with either 
schizophrenia or bipolar disorder who have episodes of agitation (BXCL501-105) and one 
completed trial for the treatment of agitation in subjects with dementia (BXCL501-303). 
IGALMI is also being evaluated in 7-day multiple ascending dose trial in healthy volunteers 
(BXCL501-106) to support repeat dosing in other indications. 
Tachyphylaxis, Tolerance, and Withdrawal 
There has not been evidence of tachyphylaxis, tolerance, or withdrawal in preclinical or clinical 
studies with BXCL501.  In preclinical studies, rat EEG showed no evidence of tachyphylaxis or 
tolerance to daily IP dexmedetomidine over 3 weeks. The first dose and 21st consecutive days 
dose showed no difference in EEG effects in rat. Additionally, toxicology data with twice daily 
dose administrations at maximum tolerated doses that produce much greater exposure to 

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dexmedetomidine than the human exposure from the approved label dosing of IGALMI have not 
demonstrated tachyphylaxis for sedation.  
Studies of prolonged high-dose, constant-rate IV exposure of dexmedetomidine (Precedex) to 
maintain sedation or treat delirium have been performed. In many of these studies, there is no 
evidence of tolerance or withdrawal after cessation of drug administration (Shehabi et al., 2004; 
Shehabi et al., 2019). However, in some case studies, some evidence for withdrawal and 
tolerance was reported (Burbano et al., 2012; Bouajramet et al., 2019). Unfortunately, these 
uncontrolled retrospective studies often confuse recurrence of the condition (like agitation) to be 
withdrawal effects and even support this assertion, claiming reversibility by substituting another 
alpha-2 agonist as proof. It is difficult to differentiate between re-emergence of the underlying 
agitation when treatment from dexmedetomidine is stopped from withdrawal effects.  Lastly, 
although BioXcel has not specifically analyzed for evidence of tolerance or tachyphylaxis, we 
have studied doses of 240 
 BID for a total of 480 
daily for one week in opiate withdrawal 
with no evidence of tachyphylaxis/tolerance or withdrawal by AE report or CV effects. While 
not definitive, it is suggestive that high doses of IGALMI are not associated with robust 
tolerance or withdrawal.  
Study Rationale 
In response to the FDA request to examine the potential for tachyphylaxis, tolerance and 
withdrawal associated with IGALMI, BioXcel is planning to study withdrawal, tachyphylaxis, 
tolerance after dosing as needed (PRN) for 7 days in subjects with bipolar disorder or 
schizophrenia who are agitated frequently (at least 3 days a week) in an inpatient setting. This 7-
day treatment period will be followed by a 3 day follow up period during which time no 
IGALMI will be administered in an effort to characterize any potential withdrawal. 
6.2. 
Description 
Dexmedetomidine hydrochloride is the active S-enantiomer of medetomidine. IGALMI is a 
sublingual film comprised of dexmedetomidine and the following inactive ingredients: 
Polyethylene Oxide, Hydroxypropyl Cellulose, Sucralose, Peppermint Oil, , and FD&C Blue #1 
colorant. 
No special transport or storage conditions are required for IGALMI. Packaged films should be 
stored at 20°-25°C (68°-77 °F) with excursions permitted between 15°-30°C (59°-86°F). 

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7.
OBJECTIVES AND ENDPOINTS
7.1. 
Primary Objective 
To characterize tachyphylaxis, tolerance and withdrawal after 7 days of PRN treatment with 
IGALMI for agitation associated with schizophrenia or bipolar disorder.   
7.1.1. 
Endpoints in support of Primary Objective
 Primary Endpoint #1: Positive and Negative Syndrome Scale – Excited Component 
(PEC) reduction from pre-dose to 2 hours post-dose for all doses administered.
 Primary Endpoint #2: Clinical Global Impression-Improvement (CGI-I) at 2 hours post-
dose for all doses administered. 
 Secondary Endpoint: Withdrawal phenomenon based on adverse events (AEs) and 
hemodynamic effects during the 3-day follow-up assessed as the percentage of subjects 
observed with the occurrence of AEs including tachycardia, systolic hypertension, 
nausea, or vomiting and the emergence of any new AE
-
day off treatment period. 
 Exploratory Endpoint #1: Percentage of PEC responders after the first dose compared to 
the percentage of responders after the last dose. Responders are those with at least a 40% 
reduction in PEC total score from pre-dose at 2 hours post-dose of study treatment. 
 Exploratory Endpoint #2: Percentage of Clinical Global Impression-Improvement (CGI-
I) responders after the first dose compared to the percentage of responders after the last 
dose. Responders are those with a CGI-I score of 1 or 2 at 2 hours post-dose of study 
treatment. 
 Exploratory Endpoint #3: Clinical Global Impression-Severity (CGI-S) at pre-dose and 
change from baseline for all doses administered.
7.2. 
Secondary Objective 
To determine the safety and tolerability of IGALMI under the studied dosing conditions.  
7.2.1. 
Endpoints in support of Secondary Objective 
 Occurrence of AEs 
Observed, change from baseline, and change from pre-dose in vital signs 
 Observed and change from baseline in 12-lead electrocardiograms (ECGs) parameters, 
and overall assessment 
 Observed, change from baseline, and change from pre-dose in Agitation-Calmness 
Evaluation Scale (ACES) 

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8.
STUDY DESIGN
8.1. 
Overall Study Design and Plan 
This is an in-clinic, single arm, open label study assessing tachyphylaxis/tolerance and 
withdrawal following repeated doses of IGALMI in adult males and females (18 to < 65 years 
old) with agitation associated with schizophrenia or bipolar disorder. Subjects will be screened 
for eligibility within 15 days of first dose and no study procedures will occur unless subjects 
provide written informed consent. Subjects must remain in-clinic during screening period and 
throughout the duration of the study.  
Subjects will self-administer IGALMI 180 µg for an agitation episode that reaches a pre-dose 
PEC criterion of 14 or greater, as determined by a trained rater. IGALMI 180 µg film will be 
self-administered sublingually by the subject, after receiving instructions and under the 
supervision of staff. The film will be retained in the sublingual cavity until dissolved. Subjects 
will also be periodically evaluated for local irritation around the area where the film is 
placed.  Safety assessments will be conducted before and after each dose. All efforts should be 
made to have the subject perform all assessments as per protocol.  If the subject’s agitation is 
recurrent or persistent, repeat doses of 90 µg may be administered (no more than 2 doses within 
a 12-hour period) in the absence of any safety concerns or adverse events.  Should the subject’s 
status warrant it, standard of care rescue treatment for agitation can also be initiated, preferably 
after the post dose 2-hour assessments are completed.    
Safety, tolerability, and efficacy will be measured throughout the treatment period. Safety and 
tolerability assessments including vital signs will be monitored pre-dose and post-dose for each 
dose administered.  Any abnormal vital sign measurement or physical examination finding 
deemed clinically significant by the investigator will be repeated.   
All subjects will receive single doses of 180 µg of IGALMI as needed for the treatment of 
agitation over a period of 7 days. As noted above, in the event of persistent or recurrent agitation, 
investigators may choose 
-hour time point in the absence of 
dose-limiting adverse events or safety concerns. A maximum of 2 re-doses will be allowed in a 
12-hour period. 
Safety and tolerability will be monitored during the follow up period of 3 days post last dose 
(Day 7). Hemodynamic parameters and AEs will be recorded in addition to any agitation 
episodes that occur during follow up. During follow up period, agitation episodes will be rated 
pre-dose using the PEC scale but not treated with IGALMI, rather, during the follow up period, 
subjects will be treated with their standard of care (SOC).   
8.2. 
Study Sites 
The study will take place at up to 3 sites in the US. 

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9.
SUBJECT POPULATION
Selection of study population: 
9.1.
Inclusion Criteria
A subject will be eligible for inclusion in the study if he or she meets the following criteria:
1. Male and female subjects between the ages of 18 to < 65 years. 
2. Subjects who have met DSM-5 criteria for schizophrenia, schizoaffective, or 
schizophreniform disorder or bipolar I or II disorder. 
3. Subjects who are judged to be clinically agitated at pre-
the 5 items (poor impulse control, tension, hostility, uncooperativeness, and excitement) 
comprising the Positive and Negative Syndrome Scale – Excited Component (PEC). 
4. Subjects who are currently moderate to severely agitated at least 3 days a week. 
5. Subjects who read, understand, and provide written informed consent. 
6. Subjects who are in good general health prior to study participation as determined by a 
detailed medical history and in the opinion of the Principal Investigator. 
7. Female subjects, 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. 
8. Subjects must be willing to remain in-clinic for the duration of the study. 
 
9. Subjects must have been taking medication for the treatment of schizophrenia or bipolar 
disorder for at least 30 days prior to screening. 
 
 
9.2. 
Exclusion Criteria 
A subject will be excluded from the study if he or she meets the following criteria: 
1. Subjects 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, barbiturates, antihistamines, sedating 
antidepressants, triptans, opioids, antipsychotics, and antihypertensives in the 4 hours 
before study treatment.  
3. Subjects with congenital prolonged QT syndrome. 

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4. Prior treatment with IGALMI. 
5. Suicidality as assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). A 
significant risk of suicide based on the Investigator’s clinical opinion or a history of an 
actual suicide attempt in the last year are also exclusionary; or self-injurious behavior 
that is active.  
6. Female subjects who have a positive pregnancy test at baseline or are breastfeeding. 
7. Subjects 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. 
8. History of syncope or other syncopal attacks, current evidence of hypovolemia, 
orthostatic hypotension (average of 1, 3 and 5 min measurements), a pre-dose heart rate 
of  < 55 beats per minutes or systolic blood pressure <110 mmHg or diastolic BP <70 
mmHg. 
9. Subjects with clinical 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. 
10. Subjects 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.
11. Subjects who have received an investigational drug within 30 days prior to the current 
agitation episode. Subjects who are considered by the investigator, for any reason, to be 
an unsuitable candidate for receiving dexmedetomidine; e.g., subjects with a history of 
allergic reactions to dexmedetomidine. 
9.3. 
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 
In this open label, single arm study, all subjects will receive single doses of 180 µg of IGALMI 
as needed for the treatment of agitation over a period of 7 days. 
10.2. 
Identification of Investigational Product 
Commercial foil pouches of IGALMI will be supplied to the sites.  IGALMI is 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.
Individual film appearance is as follows:  
 180µg – Blue 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, subjects 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 subject will self-administer under the supervision of a trained staff member. If the 
subject 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, 
film cut in half) after the 2-hour timepoint in the absence of dose-limiting adverse events 
or safety concerns. A maximum of 2 re-doses will be allowed in a 12-hour period. 
10.4. 
Storage 
No special transport or storage conditions are required for IGALMI. Packaged films should be 
stored at 20°-25°C (68°-77 °F) with excursions permitted between 15°-30°C (59°-86°F).  
10.5. 
Labeling  
Commercial labeled180 
 IGALMI pouches will be used for this study, including lot number 
and expiration date. 
10.6. 
Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of study drug, including the date, quantity, batch or code number, and identification 
of subjects (subject number and initials) who received study drug. The investigator will not 
supply study drug to any person except those named as sub-investigators on the FDA 1572, 
designated staff, and subjects in this study. The investigator will not dispense study drug from 
any sites other than those listed on the FDA 1572. Study drug may not be relabeled or reassigned 
for use by other subjects. 
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. 

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If a repeat (90 
 dose is administered any half unused film must be retained in the original 
opened pouch, for drug accountability. 
10.7. 
Treatment Compliance 
Drug accountability will be performed by site personnel and the drug administration compliance 
is expected to be 100%. 
10.8. 
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.
10.9. 
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.  
10.9.1. 
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.  
10.9.2. 
Prohibited Therapies 
The following medications are prohibited within the 4 hours before dosing of study treatment 
and 2 hours after dosing:  
Sedative/hypnotics, barbiturates, anxiolytics (including benzodiazepines), antihistamines (e.g. 
diphenhydramine), sedating antidepressants (mirtazapine, trazodone), triptans (e.g. sumatriptan), 
opioids, antipsychotics, antihypertensives. 
If any of the above were used for the indication of insomnia, then that must be clearly recorded 
in CRF and source documents. 
All assessments should be completed prior to any of the medications in section 10.9.2 being 
taken.  If not possible, this should be clearly recorded in source documents. 
Subjects should not begin a new treatment regimen for their schizophrenia or bipolar disorder 
during the conduct of the study. 

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11.
STUDY PROCEDURES
Subjects will provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
The schedule of events to be performed during the study is provided in Table 3.1. 
11.1. 
Screening  
Subjects must be screened into the study before dosing.  
The following procedures will be performed at Screening (refer to the Schedule of Events 
Table 3.1): 
Obtain written informed consent 
Review inclusion and exclusion criteria 
Collect demographic information
 Record medical history  
 Physical examination including weight, height, body mass index 
 ECG  
 Neurological examination  
 Urine pregnancy test for all females of childbearing potential 
 UDS and Breathalyzer 
 Safety laboratory assessments
 Vital signs (Resting/Recumbent and Orthostatic) 
 Heart rate
 C-SSRS 
 Record concomitant medication use (including prior and current therapies (e.g., 
prescription and non-prescription medications)  
 Assess and review AEs  
The Screening Visit may be conducted over more than one day; however, all procedures must be 
completed prior to subject enrolment and within 15 days of first dose. 
Screen Failures: Subjects who fail inclusion and/or exclusion criteria may be rescreened for the 
study at PI and Sponsor discretion. Subjects may only be rescreened one time.  
If re-screen occurs greater than 30 days from Screening visit, all Screening assessments must be 
completed. If less than 30 days, re-screen assessments will be completed on a case-by-case basis 
with PI and Sponsor discretion.   
11.2. 
Days 1 – 7, Pre-Dose 
The following procedures will be performed prior to dosing: 
 Review inclusion and exclusion criteria 

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 Assess and record AEs  
 Record concomitant medication use 
Urine pregnancy test for all females of childbearing potential (only at pre-dose Day 1, 
first agitation episode only).
UDS and breathalyser (only at pre-dose Day 1, first agitation episode only) 
Vital signs (Resting/Recumbent and Orthostatic) (prior to agitation episodes if possible) 
 Heart rate (prior to agitation episodes if possible) 
 CGI-S 
 PEC (within 15 min of dosing) 
 ACES Day (within 15 minutes prior to  dosing) 
 Trial drug administration 
Upon completion of the pre-dose procedures, the subject will be enrolled to study treatment 
(180µg IGALMI), study drug administration will occur, and the following procedures will be 
performed 2 hours post-dose (+/- 30 minutes) (Refer to the Schedule of Events, Table 3.1, for 
specific time points): 
11.3. 
Days 1 – 7, Post-Dose Assessments 
 Assess and record AEs 
 Record concomitant medication use 
 Vital Signs (Resting/Recumbent and Orthostatic) 
 Heart rate
 ECG (only Day 1, 2 hours post first dose) 
ACES (2 hours post every dose) 
 CGI-I 
 PEC 
In the event of persistent or recurrent agitation, investigators may choose 
after the 2-hour time point in the absence of dose-limiting adverse events or safety concerns. A 
maximum of 2 re-doses will be allowed in a 12-hour period. 
11.4. 
Days 8 – 10, Follow Up/Early Termination 
The following procedures will be performed on Days 8 – 10: 
 Assess and record AEs 
 Record concomitant medication use 
 Vital signs (Resting/Recumbent and Orthostatic) (prior to agitation episodes if possible). 
If no agitation episode occurs resting vital signs and orthostatic vital signs must be 
collected daily during this period 

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 Heart rate (prior to agitation episode if possible). If no agitation episode occurs heart rate 
must be collected daily during this period
 ECG  (to be performed during follow up/Early Termination period regardless if subject 
had an agitation episode. If subject was dosed on Day 7 ECG should be collected at least 
24 hours post their last dose on Day 7)  
 PEC (before and after dosing with subjects’ SOC medication at the time of an agitation 
episode) 

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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. 
12.1.1. 
PANSS – Excitatory Component (PEC) 
Assessment of drug effect on acute agitation will be done using the Positive and Negative 
Syndrome Scale – Excited Component (PEC) according to the Schedule of Events (Table 3.1). 
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. 
12.1.2. 
Clinical Global Impressions-Improvement (CGI-I) 
Drug response on agitation will be evaluated by the Clinical Global Impressions – Improvement 
(CGI-I). It will be performed according to the Schedule of Events (Table 3.1). 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 
CGI-I will be focused on the severity of agitation rather than the severity of the overall illness of 
schizophrenia or bipolar disorders. 
12.1.3. 
Clinical Global Impression-Severity (CGI-S) 
Clinical Global Impression of Severity (CGI-S) will be rated based upon the severity of agitation 
at Pre-dose (immediately prior to start of dosing) and performed according to the Schedule of 
Events (Table 3.1). 
Severity of agitation will be assessed based on following scale: 
0 = Not assessed 
1 = Normal not at all symptomatic 
2 = Mildly symptomatic-low level of symptoms-little interference in social functioning 
3 = Moderately symptomatic-some prominent symptoms-some interference in functioning 
4 = Severely symptomatic- very marked symptoms make it difficult for subjects to engage with 
others 

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12.2.
Safety
Safety will be assessed during the study by the monitoring and recording of AEs, vital sign 
measurements (systolic and diastolic blood pressures, heart rate measured as pulse, respiratory 
rate, and temperature), ECGs, and ACES scores physical examination findings according to the 
Schedule of Events (Table 3.1).  
12.2.1. 
Adverse Events 
12.2.1.1. 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

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Medical and scientific judgment should be used in deciding whether it is appropriate to consider 
other situations serious, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent another of the outcomes listed in the definition previously. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
An elective hospital admission to treat a condition present before exposure to the study drug or a 
hospital admission for a diagnostic evaluation of an AE does not qualify the condition or event as 
an SAE. A newly diagnosed pregnancy in a subject who has received a study drug is not 
considered an SAE unless it is suspected that the study drug interacted with a contraceptive 
method and led to the pregnancy; however, the medical monitor should be made aware of a 
newly diagnosed pregnancy as soon as possible after site notification. A congenital anomaly in 
an infant born to a mother who was exposed to the study drug during pregnancy is an SAE. 
12.2.1.2. 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. 
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. 
12.2.1.3. 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 MedDRA will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
The investigator or designee must report any AE that meets the criteria for an SAE 
(Section 12.2.1.1) to BioXcel’s vendor designee within 24 hours of first becoming aware of the 
event by e-mail or fax using an SAE report form. At the time of first notification, the investigator 
or designee should provide at a minimum the following information if available: 
 Investigator information (name, phone, fax, e-mail) 
 Protocol number 

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 Subject’s study identification and initials 
 Subject’s date of birth 
Date of dose of study drug 
Time and date of occurrence of the event 
A brief description of the event, outcome to date, and any actions taken 
Any missing or additional relevant information about the SAE should be provided in a written 
follow-up SAE report form. The investigator should also ensure that any additional information 
requested about the event (e.g., hospital reports, autopsy reports) is provided as soon as it is 
available. 
The investigator is required to comply with applicable regulations (including local laws and 
guidance) regarding the notification of the institutional review board (IRB). 
SAEs will be reported to BioXcel's vendor designee (s) as per the current Safety Management Plan 
associated with this study.
12.2.1.3.1. 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. 
12.2.1.3.2. Assessment of Relationship 
The investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process but is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Not related:
An AE with 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.) 

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Unlikely/Remotely 
related:
An AE, including a clinical laboratory test abnormality, with a 
temporal relationship to administration of study drug that makes 
a causal relationship improbable and in which other drugs, 
events, or underlying disease provide plausible explanations. 
Possibly related: 
An AE with a reasonable time sequence to administration of 
study drug but that could also be explained by concurrent 
disease or other drugs or events. Information on drug withdrawal 
may be lacking or unclear. 
Probably related: 
An AE with a reasonable time temporal sequence from 
administration of the study drug; or the AE follows a known 
pattern of or response to the study drug; or an alternative 
explanation (e.g. concomitant disease, environment factors, 
and/or concomitant medications) is less likely than attribution to 
the study drug; or the AE diminishes or disappears upon 
cessation of study drug.  
Definitely Related: An AE occurring in a plausible time relationship to 
administration of study drug and that cannot be explained by a 
concurrent disease or other drugs or events. The response to 
withdrawal of the drug (dechallenge) is clinically reasonable.
12.2.1.3.3. 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. 
12.2.1.4. 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. 
12.2.2. 
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.  
12.2.3. 
Laboratory Safety Assessments  
Samples for the following laboratory tests will be collected at Screening. 

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Local Labs: 
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 
12.2.4. 
Vital Signs 
Resting vital signs, including systolic, diastolic blood pressure, and heart rate (measured as 
pulse) will be measured after the subject has been in a recumbent position for at least 5 minutes 
at the 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.
At indicated timepoints orthostatic measurement of systolic, diastolic blood pressure, and heart 
rate will be measured after the subject has been standing for a total of 1, 3 and 5 minutes at the 
time points specified in the schedule of events (Table 3.1). Temperature and respiratory rate will 
be recorded when orthostatic measurement is indicated in the schedule of events and are not 
required to be measured at resting vital sign timepoints.  
If the first measurement of vital signs (SBP, DBP, and pulse) shows the following, vital signs 
will be measured again in triplicate (same arm, separated by at least 1 minute) for: 
 Systolic Blood Pressure <90 mmHg 
 Diastolic Blood Pressure <60 mmHg 
 Pulse <60 bpm 
12.2.5. 
ACES   
The Agitation-Calmness Evaluation Scale (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 (Katagiri et al, 2013). 

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12.2.6. 
Electrocardiogram 
Triplicate (30-60 sec intervals) 10-second (sec) surface 12-lead ECG will be performed at the 
timepoints specified in the Schedule of Events (Table 3.1). Date and time of ECG, ventricular 
heart rate (beats/minute), P-R interval, QRS calculated. Normal ranges for ECG parameters will 
be as per the CRO’s current values for these ranges. To determine the presence of QT 
prolongation, the ECG is to be read, and the site staff will calculate the QTcF values immediately 
after the ECG has been performed. QTcF prolongation is present if the QTcF value is >450 msec 
for males and > 470 msec for females o
 
12.2.7. 
Physical Examination 
A standard physical examination will be performed at Screening. 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. 
12.2.8. 
Concomitant Medications 
Concomitant medications will be reviewed and documented each day during the study. 

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13.
STATISTICAL METHODS
13.1. 
General Considerations 
A Statistical Analysis Plan (SAP) that describes the details of the analyses to be conducted will 
be finalized before database lock. 
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum 
values for continuous variables, and number and percentage of subjects in each category for 
categorical variables) will be provided for evaluated variables.
Planned analyses are descriptive in nature and no inferential statistics will be applied.  
13.2. 
Analysis Populations 
The following analysis populations are planned:  
Enrolled Population: All subjects that complete the pre-dose procedures for first dose and are 
deemed eligible to receive study treatment (180µg IGALMI). 
Safety Population: All Enrolled Population subjects who receive at least one dose of study drug. 
Full Analysis Set (FAS) Population: All Enrolled Population subjects who receive at least one 
dose of study drug and have at least one dose with a pre-dose and post-dose PEC Score, or at 
least one CGI-I Score, or at least one CGI-S Score after first dose. 
13.3. 
Statistical Analyses 
Analyses will be descriptive in nature. All available data will be included in the analyses. 
Missing data is not anticipated at the 2 hour primary time point.  
Continuous variables will be summarized using descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum). For categorical variables, frequencies and percentages will be 
presented. 
Individual data will be listed by subject and time of assessment. Plots of individual subject 
values over time will be provided. As appropriate, additional figures may be created to 
supplement any of the analyses. 
Details of the statistical analyses will be provided in the Statistical Analysis Plan which will be 
finalized prior to database lock. 
13.3.1. 
Subject Disposition and Demographic Characteristics 
Subject disposition will include the number of subjects screened and the number and percentage 
of subjects included in each analysis population. The frequency and percentage of subjects who 
withdraw or discontinue from the study, along with the reason for withdrawal or discontinuation, 
will also be presented for the Enrolled Population. 
Demographics and baseline characteristics, including age, sex, race, weight, height, and body 
mass index (BMI), will be summarized for the Enrolled Population. 
13.3.2. 
Tachyphylaxis and Withdrawal Analyses 
Tachyphylaxis/Tolerance assessment:  Tachyphylaxis/tolerance assessment will be conducted 
on the FAS Population. PEC scores will be summarized by observed and change from baseline 
and pre-dose values using descriptive statistics. CGI-I and CGI-S scores will be summarized 

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13.4.
Sample Size Determination
There is no hypothesis testing in this study due to its open label nature. The sample size is based 
on clinical experience and judgment relative to study design and objectives. Given the clinical 
data available to date for IGALMI, and that the nature of this exploratory study a sample size of 
at least 20 subjects on active drug should provide adequate clinical information to meet the 
objectives of the study. 

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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 
14.1.1.
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. 
14.1.2. 
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. 
14.3.1. 
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. 
14.3.2. 
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. 
14.3.3. 
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. 
14.4.1. 
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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14.4.2. 
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. 
14.4.3. 
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. 
14.5.1. 
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. 
14.5.2. 
Premature Study Termination 
The study may be terminated prematurely for any reason and at any time by the sponsor, IRB, 
regulatory authorities, or the coordinating investigator. A decision to prematurely terminate the 
study is binding to all investigators of all study sites.
Within 15 days of premature termination of a clinical study, the sponsor or designee will notify 
the IRB and regulatory authorities as required. The sponsor or designee must clearly explain the 
reasons for premature termination.

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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.
14.6.1. 
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.   
14.6.2. 
Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed, and the decision has been made 
that none of the samples needs to be reanalyzed or at the completion of the CSR. In addition, 
identifiable samples can be destroyed at any time at the request of the subject. 

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14.7.
Changes to the Protocol
This protocol cannot be altered or changed except through 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, 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.
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