A Phase 1b/2 Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Study of BXCL501 to Treat Symptoms of Acute Opioid Withdrawal in Patients With Opioid Use Disorder Who Are Physically Dependent on Opioids
Phase: PHASE1
Conditions: Opioid Withdrawal
Sponsor: BioXcel Therapeutics Inc

 
 
 
 
 
 
 
 
 
 
A PHASE Ib/2 RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, ASCENDING-DOSE STUDY 
OF BXCL501 TO TREAT SYMPTOMS OF ACUTE 
OPIOID WITHDRAWAL IN PATIENTS WITH OPIOID 
USE DISORDER WHO ARE PHYSICALLY DEPENDENT 
ON OPIOIDS 
 
NCT04470050 
11/24/2020 

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A 
PHASE 
1b/2 
RANDOMIZED, 
DOUBLE-BLIND, 
PLACEBO-CONTROLLED, 
ASCENDING-DOSE STUDY OF BXCL501 TO TREAT SYMPTOMS OF ACUTE OPIOID 
WITHDRAWAL IN PATIENTS WITH OPIOID USE DISORDER WHO ARE PHYSICALLY 
DEPENDENT ON OPIOIDS 
 
 
 
PROTOCOL NUMBER: 
BXCL501-201 
 
 
STUDY PHASE: 
Phase 1b/2 
 
 
IND NUMBER: 
140184 
 
PROTOCOL VERSION: 
3.0 
 
ORIGINAL PROTOCOL DATE: 
17 December 2019 
AMENDMENT 1 DATE 
08 May 2020 
AMENDMENT 2 DATE 
24 Nov 2020 
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 
 
A 
PHASE 
Ib/2 
RANDOMIZED, 
DOUBLE-BLIND, 
PLACEBO-CONTROLLED, 
ASCENDING-DOSE STUDY OF BXCL501 TO TREAT SYMPTOMS OF ACUTE OPIOID 
WITHDRAWAL IN PATIENTS WITH OPIOID USE DISORDER WHO ARE PHYSICALLY 
DEPENDENT ON OPIOIDS 
 
PROTOCOL NUMBER:  
BXCL501-201 
 
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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Starting on the morning of Day 6, a blinded abrupt discontinuation of active morphine will begin by 
replacing active morphine with placebo morphine.  Placebo morphine capsules will be identical in 
appearance to the morphine capsules taken during the opioid maintenance period.  On this day 
(Study Day 6), subjects will be randomized to receive either placebo or BXCL501 films administered 
twice a day (BID), approximately 12 hours apart at approximately 8am and 8pm. BXCL501-placebo or 
BXCL501 will be administered on Days 6-12 along with placebo morphine (QID).  On days 13 and 14, 
all remaining subjects will receive placebo morphine capsules (QID) and BXCL501 placebo films 
(BID).  
It is anticipated that approximately 9 cohorts will be tested (n=25 per cohort) with potential to add 
cohorts or select different doses/schedule of dosing based on ongoing safety review and medical 
monitoring. The following doses will be administered: 30 µg (Cohort 1), 60 µg (Cohort 2), 90 µg 
(Cohort 3), 120 µg (Cohort 4), and 180 µg (Cohort 5). Doses for cohorts 6-9 will be determined from 
data acquired from cohorts 1-5.  Safety and tolerability will be monitored continuously and 
summarized upon completion of each cohort by medical safety review.  Studies of opioid withdrawal 
with placebo arms are likely to have high dropout rates, thus, the dropouts prior to Day 6 may be 
replaced to ensure enough sample size entering the treatment phase.  Dropouts after Day 6 will not be 
replaced.  The study is intended to be flexible and adaptable and as such, the dosing frequency, the 
doses, and the number of cohorts of BXCL501 may be changed as a result of review of safety, 
tolerability, and efficacy data. 
Opioid withdrawal symptoms (SOWS-Gossop and COWS) will be measured throughout the inpatient 
period at Predose, 2 hours post dose, pre 2nd dose, and 2 hours post second dose.  Additional/SOWS-
Gossop/COWS may be administered at investigator discretion.  Transition to treatment for opioid use 
disorder will be offered prior to patients leaving the unit. 
The following table is representative of cohorts 1-5 only: 
 
BID = twice a day; PO = oral/by mouth; QID = four times a day 
Vital Signs, SOWS-Gossop, COWS, pulse oximetry and electrocardiogram (ECG) with rhythm strip 
will be measured as per the schedule of assessments (Table 2). BXCL or placebo will be 

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self-administered sublingually under staff observation and subjects will be allowed fluids as desired 
15 minutes after completion of dosing. Safety and tolerability assessments will be continued until the 
morning of Day 14 (day of discharge). 
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. 
Diagnosis and Main Criteria for Eligibility:  
Inclusion Criteria 
1. Male and female subjects who are 18 years of age to less than 65 years of age. 
2. Meets criteria for moderate to severe opioid use disorder as per Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by the 
Mini-International Neuropsychiatric Interview (MINI) with physiological dependence as 
evidenced by a Clinical Opiate Withdrawal (COWS) score of >5 or a positive naloxone 
challenge upon admission on Day 1. 
3. Subjects who can read, understand and provide written informed consent. 
4. Women of childbearing potential must have a negative pregnancy test and agree to be abstinent 
or use an acceptable method of contraception for the duration of the study. 
Exclusion Criteria 
1. Positive urine pregnancy test at screening or when tested or currently breast feeding. 
2. Clinically significant history of cardiac disease, screening and baseline heart rate of <55 beats 
per minutes or systolic blood pressure <110 mmHg or diastolic blood pressure <70 mmHg. 
3. History or presence of a significant medical disease or disorder which, in the opinion of the 
investigator, increases the risk or may confound the interpretation of study measures, as 
confirmed by screening laboratory results. 
4. Hepatic dysfunction (marked by ascites, or bilirubin >10% above the upper limit of normal 
[ULN] or liver function tests >3 x ULN) at the screening visit. 
5. Acute active Hepatitis B or C as evidenced by positive serology and aspartate aminotransferase 
(AST)/alanine aminotransferase (ALT) >2 x ULN. 
6. Clinically significant abnormal ECG findings such as second- or third-degree heart block, 
uncontrolled arrhythmia, or QTcF (Fridericia correction formula) interval >450 msec for males, 
and >470 msec for females at screening or prior to dosing. 
7. Any psychiatric disorder that would compromise ability to complete study requirements. 
8. Currently meets DSM-5 criteria for substance abuse disorder, moderate or severe for any 
substance other than opioids, caffeine, or nicotine and/or current physical dependence on drugs 
that pose risk of withdrawal that requires medical management such as alcohol or 
benzodiazepines.  
9. History of suicidal behavior within the last 1 year prior to screening. 
10. Participation in a clinical trial of a non-FDA-approved pharmacological agent within 30 days 
prior to screening. 
11. Use of any excluded medication at screening or anticipated/required use during the study 
period. 
12. Subjects with a history of intolerance to morphine. 
13. Any finding that, in the view of the principal investigator, would compromise the subject’s 
ability to fulfill the protocol visit schedule or visit requirements. 
 

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Test Product, Dose, and Mode of Administration:  
BXCL501 30 µg, 60 µg, 90 µg, 120 µg and 180 µg doses will be used for cohorts 1-5 and have been 
developed as a thin film formulation of DEX for sublingual (SL) administration. The product is a 
small, solid-dose film formulation designed to completely dissolve in the SL space within 1-3 minutes.  
Doses for cohorts 6-9 were formulated in the same manner; however, doses for cohorts 6-9 will be 
determined from data acquired from cohorts 1-5. 
Reference therapy, dosage and mode of Administration: Matching placebo films to be taken 
sublingually as described above. 
Duration of Treatment: 30 mg QID or 5x/day Morphine and BXCL501-placebo: 5 days;  
BID BXCL501 or BXCL501-placebo and morphine placebo: 7 days;  
BXCL501-placebo and morphine placebo: 2 days 
Criteria for Evaluation:  
Efficacy assessment: Determine the preliminary efficacy of sublingual dosing of BXCL501 in the target 
population compared to placebo, as measured by improved peak SOWS-Gossop scores.  
Safety and tolerability assessments: COWS, SOWS-Gossop, adverse events (AEs), clinical laboratory 
tests, ECG with rhythm strip, pulse oximetry and vital signs will be monitored for tolerability 
assessment. The ACES assessment will also be administered as a safety measure. All observed and 
volunteered AEs will be recorded. The relationship of AEs to the study drugs will be graded as not 
related, unlikely/remotely related, possibly related, probably related or definitely related by the 
investigators. Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), 
orthostatic blood pressure, heart rate, and oxygen saturation will be measured daily throughout the 
study. The application site of the SL preparation (buccal mucosa) will be inspected for any signs of 
local irritation.  
Additional Assessments: 
• 
Demographic Data 
• 
Medical and Psychiatric History 
• 
Prior and Concomitant Medication 
• 
Physical Examination 
• 
Suicidality 
• 
Pregnancy 
Statistical Analysis:  
Primary Outcome: Safety and tolerability of ascending doses of BXCL501 in subjects with OUD who 
are physically dependent on opioids. 
Secondary Outcomes: 
1) Peak SOWS-Gossop score during Days 6-14. 
2) Peak COWS score during Days 6-14 
3) Average COWS scores per day for Days 6-14 (an average will be calculated for each day in order to 
assess time course of withdrawal symptoms).  
4) Average SOWS-Gossop scores per day on Days 6-14. 
5) Time to dropout after discontinuation of morphine maintenance (Days 6-14). 
6) Percentage of subjects dropping out after discontinuation of opioid maintenance within each 
treatment group between Days 6-14 

 
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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 ...........................................................................................12 
5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
6 
INTRODUCTION ......................................................................................................18 
6.1 
Background and Rationale ................................................................................18 
6.2 
Non-Clinical Pharmacology ..............................................................................20 
6.3 
Clinical Experience and Pharmacokinetics .......................................................20 
7 
STUDY DESIGN .......................................................................................................24 
7.1 
Overall Study Design and Plan .........................................................................24 
7.2 
Dose Justification ..............................................................................................25 
7.3 
Study Sites .........................................................................................................26 
8 
SUBJECT POPULATION .........................................................................................27 
8.1 
Selection of Study Population ...........................................................................27 
Inclusion Criteria ...............................................................................................27 
Exclusion Criteria..............................................................................................27 
8.2 
Removal of Subjects from Therapy or Assessment ..........................................28 
9 
STUDY TREATMENTS............................................................................................29 
9.1 
Method of Assigning Subjects to Treatment Groups ........................................29 
9.2 
Identification of Investigational Product ...........................................................29 
9.3 
Identification of Non-investigational Product ...................................................29 
9.4 
Storage ...............................................................................................................29 
9.5 
Labeling .............................................................................................................30 
9.6 
Drug Accountability ..........................................................................................30 
9.7 
Blinding and Unblinding Treatment Assignment .............................................30 
9.8 
Selection of Dose in the Study ..........................................................................30 
9.8.1 Treatment Compliance ..........................................................................30 
9.8.2 Concomitant Medications ......................................................................31 

 
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9.8.3 Permitted Therapies ...............................................................................31 
9.8.4 Prohibited Therapies ..............................................................................31 
10 STUDY PROCEDURES ............................................................................................33 
10.1 Screening (within 30 days prior to inpatient admission) ...................................33 
10.2 Patient Stabilization Phase Study Day 1 (specific assessments on Study Day 1)34 
10.3 Patient Stabilization Phase Study Days 2, 3, 4, and 5  
 
(morphine maintenance phase of the study) ......................................................34 
10.4 Randomization Study Day 6 ..............................................................................35 
10.5 Treatment Phase Study Days 7-12 ....................................................................35 
10.6 Post Treatment Phase or Early Termination Days 13-14 ..................................36 
10.7 Follow-up Period Day 21 (1 week after the end of the study) ..........................36 
11 STUDY ASSESSMENTS ..........................................................................................38 
11.1 Efficacy .............................................................................................................38 
11.1.1 Clinical Opiate Withdrawal Scale .........................................................38 
11.1.2 Short Opiate Withdrawal Scale of Gossop (also -Gossop) ...................38 
11.2 Pharmacokinetics ...............................................................................................38 
11.2.1 Sample Collection and Processing ........................................................38 
11.2.2 Sample Storage ......................................................................................38 
11.2.3 Sample Shipping ....................................................................................39 
11.2.4 Analytical Procedures ............................................................................39 
11.2.4.1 Bioanalytical Sample Analyses .................................................39 
11.2.4.2 Bioanalytical Methodology .......................................................39 
11.3 SAFETY ............................................................................................................40 
11.3.1 Adverse Events ......................................................................................40 
11.3.1.1 Adverse Event Definitions ........................................................40 
11.3.1.2 Eliciting and Documenting Adverse Events .............................41 
11.3.1.3 Reporting Adverse Events.........................................................41 
11.3.1.4 Follow-up of Adverse Events....................................................43 
11.3.2 Laboratory Safety Assessments .............................................................44 
11.3.3 Vital Signs .............................................................................................44 
11.3.4 Electrocardiogram .................................................................................44 

 
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11.3.5 Physical Examination ............................................................................45 
11.3.6 Agitation and Calmness Evaluation Scale .............................................45 
11.3.7 Timeline Follow back ............................................................................45 
11.3.8 Concomitant Medications ......................................................................45 
12 STATISTICAL METHODS .......................................................................................46 
12.1 General Considerations .....................................................................................46 
12.2 Analysis Populations .........................................................................................46 
12.3 Statistical Analyses ............................................................................................46 
12.3.1 Subject Disposition and Demographic Characteristics .........................46 
12.3.2 Efficacy Analyses ..................................................................................46 
12.3.2.1 Primary Efficacy Endpoint ........................................................46 
12.3.2.2 Secondary Efficacy Endpoints ..................................................47 
12.3.3 Safety Analyses .....................................................................................47 
12.3.4 Pharmacokinetic Analyses ....................................................................47 
12.3.5 Interim Analyses ....................................................................................48 
12.4 Sample Size Determination ...............................................................................48 
13 STUDY CONDUCT ...................................................................................................49 
13.1 Sponsor and Investigator Responsibilities ........................................................49 
13.1.1 Sponsor Responsibilities .......................................................................49 
13.1.2 Investigator Responsibilities .................................................................49 
13.2 Site Initiation .....................................................................................................49 
13.3 Study Documents ..............................................................................................50 
13.3.1 Good Clinical Practice Documents .......................................................50 
13.3.2 Case Report Forms ................................................................................50 
13.3.3 Source Documents .................................................................................51 
13.4 Data Quality Control .........................................................................................51 
13.4.1 Monitoring Procedures ..........................................................................51 
13.4.2 Data Management ..................................................................................52 
13.4.3 Quality Assurance/Audit .......................................................................52 
13.5 Study Termination .............................................................................................52 
13.5.1 Regular Study Termination ...................................................................52 

 
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13.5.2 Premature Study Termination ...............................................................53 
13.6 Study Site Closure .............................................................................................53 
13.6.1 Record Retention ...................................................................................53 
13.6.2 Sample Retention ..................................................................................54 
13.7 Changes to the Protocol .....................................................................................54 
13.8 Use of Information ............................................................................................54 
14 FINAL CLINICAL STUDY REPORT ......................................................................55 
15 ETHICAL AND LEGAL CONSIDERATIONS ........................................................56 
15.1 Declaration of Helsinki and Good Clinical Practice .........................................56 
15.2 Subject Information and Informed Consent ......................................................56 
15.3 Approval by Institutional Review Board ...........................................................56 
16 REFERENCES ...........................................................................................................57 
17 APPENDICES ............................................................................................................59 
APPENDIX A: CLINICAL OPIATE WITHDRAWAL SCALE (SAMPLE) ..................60 
APPENDIX B: SHORT OPIATE WITHDRAWAL SCALE OF GOSSOP (SAMPLE) .61 
APPENDIX C: AGITATION AND CALMNESS EVALUATION SCALE (SAMPLE) 62 
 
LIST OF TABLES 
Table 1 
Sponsor/CRO Contact Information..............................................................3 
Table 2  
Schedule of Visits and Assessments (BXCL501-201) ..............................10 
 
LIST OF FIGURES 
Figure 1 
Clinical opioid withdrawal symptoms during an escalating infusion of 
dexmedetomidine (10 subjects) versus placebo (5 subjects) .....................22 

 
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5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ACES 
Agitation and Calmness Evaluation Scale 
AUC 
area under the concentration-time curve 
BAL 
breath alcohol level 
BID 
twice a day 
COWS 
Clinical Opiate Withdrawal Scale 
Cmax 
maximum concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DBP 
Diastolic blood pressure 
Dex or DEX 
Dexmedetomidine 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practices 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MINI 
Mini-International Neuropsychiatric Interview 
mL 
milliliter 
mm 
millimeters 
mmHg 
millimeters of mercury 
OUD 
Opioid Use Disorder 
PEC 
Positive and Negative Syndrome Scale – Excited Component 
PK 
Pharmacokinetic 

 
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Abbreviation 
Definition 
PP 
Per Protocol 
QID 
four times a day 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SL 
Sublingual  
SOWS-Gossop 
Short Opiate Withdrawal Scale of Gossop 
TEAE 
treatment-emergent adverse event 
TLFB 
Timeline Followback 
ULN 
upper limit of normal 
 
 

 
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6 
INTRODUCTION 
6.1 
Background and Rationale 
Dependence on opioid drugs is a major health and social issue in most societies. Almost 1/3rd of 
U.S. adults reported use of prescription opioids on the 2015 National Survey on Drug Use and 
Health (Han et al., 2017).  In the 2015 Survey, researchers interviewed over 50,000 adults about 
their use of opioids in the past 12 months. Based on these results, researchers estimated the 
following for civilian noninstitutionalized adults: 38% (equivalent to 92 million Americans) had 
used prescription opioids in the past year, 5% (12 million) misused opioids, and approximately 
1% or 2 million Americans have an opioid use disorder (OUD). According to the Centers for 
Disease Control and Prevention, opioid overdose deaths rose from 8,048 in 1999 to 47,600 in 
2017 (Scholl et al., 2019). The effects of the opioid crisis are cumulative and costly for our 
society—an estimated $504 billion a year in 2015—placing burdens on families, workplaces, the 
health care system, states, and communities (Office of the Surgeon General, 2018).  The opioid 
crisis is being driven by three trends: 1) an increase in prescription opioid overdose deaths since 
1999; 2) the four-fold increase in heroin overdoses since 2010; and (3) the tripling death rate for 
synthetic opioids like fentanyl since 2013. As a result, the number of people dying from opioid 
overdoses has increased dramatically (Rudd et al., 2016). 
Treatment is central to the reduction of the harms incurred by individuals and the community 
from opioid use disorder. Managed withdrawal, or detoxification, by itself is not an effective 
treatment for opioid use disorder (Lipton and Maranda, 1983; Mattick and Hall, 1996). Rates of 
completion of withdrawal tend to be low, and rates of relapse to opioid use following 
detoxification are high (Broers et al, 2000; Gossop et al, 1989; Vaillant, 1988). However, 
withdrawal remains a required first step for many forms of longer‐term treatment such as 
residential rehabilitation and naltrexone maintenance (Kleber and Riordan, 1982). It may also 
represent the endpoint of an extensive period of substitution treatment such as methadone 
maintenance. As such, the availability of managed withdrawal is essential to an effective and 
comprehensive treatment system. 
A major challenge to seeking treatment for opioid use disorder is the withdrawal symptoms 
associated with cessation of opioid drug use. The signs and symptoms of the opioid withdrawal 
syndrome include irritability, anxiety, apprehension, muscular and abdominal pains, chills, 
nausea, diarrhea, yawning, lacrimation, sweating, sneezing, rhinorrhea, general weakness, and 
insomnia. Symptoms of the opioid withdrawal syndrome usually begin two to three half-lives 
after the last opioid dose, that is six to 12 hours for short half-life opioids such as heroin and 
morphine, and 36 to 48 hours for long half‐life opioids such as methadone. Following cessation 
of a short half‐life opioid, symptoms reach peak intensity within two to four days, with most of 
the obvious physical withdrawal signs no longer observable after seven to 14 days. As with the 
onset of withdrawal, the duration also varies with the half‐life of the opioid used, and the 
duration of regular use (Tetrault and O’Connor, 2009). The opioid withdrawal syndrome is rarely 
life‐threatening or associated with significant aberrations of mental state (Farrell, 1994), but the 
combination of uncomfortable symptoms and intense craving makes completion of withdrawal 
difficult for most people (Mattick and Hall, 1996; Tetrault and O’Connor, 2009. 

 
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anxiolytic, sedative, and analgesic properties. Dexmedetomidine has minimal effects on 
respiration and is a non-opioid, which contributes to its frequent use in the ICU. Patients 
receiving dexmedetomidine are easier to rouse, more co-operative, and better able to 
communicate versus patients receiving midazolam or propofol. Furthermore, dexmedetomidine 
has an acceptable safety profile with limited adverse events such as hypotension, hypertension 
and bradycardia compared to other alpha-2-adrenergic agents.  
Given these advantageous properties of dexmedetomidine that were characterized by intravenous 
administration of the drug, BioXcel Therapeutics Inc. developed a sublingual film formulation of 
dexmedetomidine as a treatment for managing opioid withdrawal. Sublingual dexmedetomidine 
is formulated as BXCL501 and offers an alternative treatment option for reducing opioid 
withdrawal symptoms in patients undergoing opioid detoxification. 
6.2 
Non-Clinical Pharmacology 
Dexmedetomidine is a highly selective alpha-2-adrenoceptor agonist on presynaptic neurons. 
The stimulation of these receptors leads to a decrease in norepinephrine release from presynaptic 
neurons with inhibition of postsynaptic activation, which attenuates central nervous system 
(CNS) arousal, especially in the locus coeruleus of the brain. 
Alpha-2 selectivity is observed in animals following slow intravenous infusion of low and 
medium doses of dexmedetomidine (10–300 µg/kg). Both alpha-1 and alpha-2 activity is 
observed following slow intravenous infusion of high doses (≥ 1000 µg/kg) of dexmedetomidine 
or in association rapid intravenous administration of dexmedetomidine (Precedex US Package 
Insert, 2016). 
Dexmedetomidine exhibits high potency and intrinsic activity at all 3 types of alpha-2-adrenergic 
receptors, A, B and C. Because all 3 receptors contribute to reducing sympathetic tone that is 
part of opioid withdrawal symptoms, dexmedetomidine may be an excellent choice of a drug that 
reduces these symptoms. Dexmedetomidine has also been studied in rats to determine its free 
brain to free plasma ratio after sublingual dosing. Dexmedetomidine exhibits 1:1 free brain to 
free plasma levels, indicating it possesses excellent qualities for a CNS drug. 
6.3 
Clinical Experience and Pharmacokinetics 
A single ascending dose study in normal, healthy volunteers was conducted with BXCL501. The 
primary objective of this study was to determine the pharmacokinetic (PK), safety, and 
tolerability of the various film strengths of BXCL501 for identification of appropriate film 
dosage strengths to be carried forward into subsequent clinical trials. The study evaluated 
3 doses (10 µg, 20 µg, 40 µg) of BXCL501 film in 4 cohorts of healthy adult male and female 
participants (n=12 subjects per cohort 2:1 randomization). Single doses up to 40 µg BXCL501 
were well-tolerated. In reviewing the safety and tolerability of the 40 µg dose, there were 
3 symptomatic subjects reporting dizziness upon standing, who had concomitant intermittent 
hypotension or bradycardia. There were no deaths or serious treatment-emergent adverse events 
(TEAEs) reported in the study. No subject was withdrawn due to a TEAE. The most frequent 
TEAE during the study was somnolence, which was reported with a slightly higher frequency at 
doses of 20 µg and 40 µg (75% each) compared to the 10 µg dose and placebo (50% each). No 
subject dosed in this study required hemodynamic interventions for maintaining BP, cardiac 

 
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7 
STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is an inpatient Phase 1b/2 randomized, double-blind, placebo-controlled, ascending-dose 
study of BXCL501 to treat symptoms of acute opioid withdrawal in subjects with opioid use 
disorder who are physically dependent on opioids. The study will assess the safety, 
pharmacokinetics, and early signs of efficacy of escalating doses of BXCL501 versus placebo 
following discontinuation of morphine maintenance in adults (≥18 to <65 years of age). 
After a 30-day screening period, eligible male and female adult subjects with OUD who are 
physically dependent on opioids and are not seeking treatment for opioid withdrawal symptoms 
will be admitted to an inpatient unit. The morphine maintenance phase will begin on Study Day 
1 and continue until the end of Study Day 5.  Approximately 9 cohorts (N=approximately 225) 
will be tested. In each cohort, approximately 25 subjects, will receive oral morphine. The total 
dose of morphine during the maintenance phase (Days 1-5) can vary at the discretion of the 
investigator, between 120 mg and 150 mg per day depending on patients abuse history and need 
for higher dose to stabilize withdrawal symptoms. In addition, these subjects will receive placebo 
films approximately 12 hours apart during the opioid maintenance phase (ie, Days 1-5) to 
simulate and thus blind treatment with BXCL501 during Days 6-12. Abrupt discontinuation of 
active morphine will begin on Day 6.  
On Study Day 6, subjects will be randomized to receive either placebo or BXCL501 
administered approximately 12 hours apart at approximately 8am and 8pm. Placebo or 
BXCL501 will be administered on Days 6-12. The AM dose will be administered at the same 
time each day (±30 minutes) and the second dose will be administered 12 hours later with a ± 30-
minute window. Patients can only be given the second dose if they are hemodynamically stable, 
not hypotensive (must be greater than 110/70 diastolic/systolic) and not bradycardic (must be 
greater than 55 bpm). Patients also cannot be given the second dose of BXCL501 if they are 
orthostatic (a drop of 20 points in either SBP or 10 points in DBP) or if they are experiencing an 
AE that when assessed by the PI precludes redosing. If a subject experiences SBP <90 mmHg; or 
DBP <60 mmHg; or HR <50 bpm, immediately prior to the next dose, the study team will hold 
administration of the study medication for that participant until resolution of these BP and HR 
parameters.  The administration hold will not exceed 2 hours.  A total of 9 cohorts will be tested 
(n=25 per cohort). Within each cohort, 20 subjects will receive active BXCL501 and 5 subjects 
will receive placebo. The following doses will be administered: 30 µg (Cohort 1), 60 µg 
(Cohort 2), 90 µg (Cohort 3), 120 µg (Cohort 4), and 180 µg (Cohort 5).  Doses for cohorts 6-9 
will be determined from data acquired from cohorts 1-5.  Safety and tolerability will be 
monitored continuously and summarized upon completion of each cohort by medical safety 
review.  Studies of opioid withdrawal with placebo arms are likely to have high dropout rates, 
thus, the dropouts prior to Day 6 may be replaced to ensure enough sample size entering the 
treatment phase.  Dropouts after Day 6 will not be replaced.  The study is intended to be flexible 
and adaptable and as such, the dosing frequency, the doses and the number of cohorts of 
BXCL501 may be changed as a result of review of safety, tolerability and efficacy data. 
Opioid withdrawal symptoms (SOWS-Gossop and COWS) will be measured throughout the 
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8 
SUBJECT POPULATION 
8.1 
Selection of Study Population 
Inclusion Criteria 
To be eligible to participate in the study, subjects must meet all of the following criteria: 
1. Male and female subjects who are 18 years of age to less than 65 years of age. 
2. Meets criteria for moderate to severe opioid use disorder as per Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by the 
Mini-International Neuropsychiatric Interview (MINI) with physiological dependence as 
evidenced by a Clinical Opiate Withdrawal (COWS) score of >5 or a positive naloxone 
challenge upon admission on Day 1. 
3. Subjects who can read, understand and provide written informed consent. 
4. Women of childbearing potential must have a negative pregnancy test and agree to be 
abstinent or use an acceptable method of contraception for the duration of the study. 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate in the study: 
1. Positive urine pregnancy test at screening or when tested or currently breast feeding. 
2. Clinically significant history of cardiac disease, screening and baseline heart rate of 
<55 beats per minutes or systolic blood pressure <110 mmHg or diastolic blood pressure 
<70 mmHg. 
3. History or presence of a significant medical disease or disorder which, in the opinion of 
the investigator, increases the risk or may confound the interpretation of study measures, 
as confirmed by screening laboratory results. 
4. Hepatic dysfunction (marked by ascites, or bilirubin >10% above the upper limit of 
normal [ULN] or liver function tests >3 x ULN) at the screening visit. 
5. Acute active Hepatitis B or C as evidenced by positive serology and aspartate 
aminotransferase (AST)/alanine aminotransferase (ALT) >2 x ULN. 
6. Clinically significant abnormal ECG findings such as second or third degree heart block, 
uncontrolled arrhythmia, or QTcF (Fridericia correction formula) interval >450 msec for 
males, and >470 msec for females at screening or prior to dosing. 
7. Any psychiatric disorder that would compromise ability to complete study requirements. 
8. Currently meets DSM-5 criteria for substance abuse disorder, moderate or severe for any 
substance other than opioids, caffeine, or nicotine, and/or current physical dependence on 
drugs that pose risk of withdrawal that requires medical management such as alcohol or 
benzodiazepines.  
9. History of suicidal behavior within the last 1 year prior to screening. 

 
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10. Participation in a clinical trial of a non-FDA-approved pharmacological agent within 
30 days prior to screening. 
11. Use of any excluded medication at screening or anticipated/required use during the study 
period. 
12. Subjects with a history of intolerance to morphine. 
13. Any finding that, in the view of the principal investigator, would compromise the 
subject’s ability to fulfill the protocol visit schedule or visit requirements. 
8.2 
Removal of Subjects from Therapy or Assessment 
All subjects are free to withdraw from participation in this study at any time for any reason and 
without prejudice. 
The investigator may terminate dosing for a subject at any time for any 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 prematurely after dosing on Day 6 will not be replaced.  
Subjects who discontinue from the study prior to Day 6 may be replaced at the discretion of the 
sponsor. 

 
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9.5 
Labeling 
Each container of study drug will be labeled with study specific information that meets all 
applicable regulatory requirements. 
9.6 
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 United States 
Food and Drug Administration Form 1572, designated staff, and subjects in this study. 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 as directed. 
9.7 
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 on 
days 6-12. BXCL501 film will be provided to the patients for self-administration by a staff 
member who will not participate in the evaluation of safety or efficacy. Study days 1-5 and 
13-14 will be conducted under single-blind conditions where the Investigator, study staff 
members, and Sponsor will know subject’s treatment assignment is BXCL501-placebo film. 
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.  
Any subject whose study drug treatment is unblinded will be discontinued and the date, time, and 
reason for the unblinding must be documented. 
9.8 
Selection of Dose in the Study 
This is a dose ranging study for the treatment of withdrawal symptoms in opioid use disorder. 
BXCL501 has not been previously tested in this population for the treatment of withdrawal 
symptoms hence a range of low to moderate/high doses has been chosen.  In addition, this dose 
range has previously been shown to be safe and efficacious in the treatment of agitation in other 
patient populations.  
9.8.1 Treatment Compliance 
All unused study medication will be returned the Sponsor.  Drug accountability will be 
performed by study site personnel.  

 
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Since treatments will be administered by site staff in this inpatient study, treatment compliance is 
expected to be 100%. 
9.8.2 Concomitant Medications 
All concomitant medications used (including over-the-counter medications and herbal and 
nutritional supplements) will be recorded in the source document and on the appropriate CRF. 
The medication name, dose, frequency, date, and indication for use must be recorded on the 
CRF.  Medications and therapies that are considered necessary for the subject’s welfare and will 
not interfere with the response to the study medication may be given at the discretion of the 
investigator. 
9.8.3 Permitted Therapies 
Concomitant medications, including prescribed anxiolytics and antidepressants, are allowed 
(unless specifically prohibited [see Section 9.8.4]) but should be limited to only those 
medications considered necessary and if the dose is stable at the time of the screening visit and 
stable throughout the study. Guaifenesin for cough, antacids for indigestion and nausea, 
Ondansetron (Zofran) for nausea/vomiting, medications for diarrhea, constipation, 
acetaminophen or ibuprofen for aches and pains.  
Lorazepam/clonazepam are permitted provided the subject is not experiencing any somnolence 
or somnolence-related AEs from investigational product use. To mitigate insomnia, zolpidem 
will be allowed only if the patient is not experiencing any somnolence or somnolence related 
AEs from the investigational product use and if the zolpidem was not administered within 2 
hours of dosing with the investigational product. Zolpidem will only be allowed if determined as 
necessary by the Investigator.  
No clonazepam or any other benzodiazepine will be allowed after day 4 throughout the study 
except for zolpidem use for insomnia only.  
To standardize the use of benzodiazepines, Investigators may prescribe clonazepam on days 1-4 
during the morphine stabilization period on the following tapering schedules: 
• Day 1: clonazepam 0.5 mg PO Q3-4 hrs. PRN opioid withdrawal (MDD=2 mg) 
• Day 2: clonazepam 0.5 mg PO Q3-4 hrs. PRN opioid withdrawal (MDD=1.5 mg) 
• Day 3: clonazepam 0.5 mg PO Q3-4 hrs. PRN opioid withdrawal (MDD=1 mg) 
• Day 4: clonazepam 0.5 mg PO once PRN opioid withdrawal (MDD=0.5 mg) 
• Day 5: No clonazepam to avoid potential benzodiazepine withdrawal 
Full or partial opioid agonists are permitted for rescue medication purposes only, and if provided, 
will discontinue the patient from study participation (see Section 9.8.4). 
9.8.4 Prohibited Therapies 
The following medications are prohibited medications: 
Sedative/hypnotics, barbiturates, antihistamines (e.g. diphenhydramine), sedating antidepressants 
(mirtazapine, trazodone), and triptans (e.g., sumatriptan) unless prescribed and stable prior to 
admission. Blood pressure lowering drugs and other alpha-2-adrenergic agonists (clonidine, 

 
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guanfacine, lofexidine) and alpha-1-adrenergic antagonists (prazosin) are prohibited.  Subjects 
already on antihypertensive medications at study entry may continue on them (provided they are 
not alpha-2 adrenergic agonists). 
If opiate full/partial agonists are required, this will be considered rescue treatment and result in 
study discontinuation. 

 
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10 STUDY PROCEDURES 
Subjects will provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
10.1 Screening (within 30 days prior to inpatient admission) 
The following procedures and assessments will be performed at Screening: 
• Obtain written informed consent. No study procedures may be performed prior to 
completion of the ICF process. 
• Review inclusion and exclusion criteria. 
• Collect demographic information. 
• Record medical and psychiatric histories, including administration of the Columbia Suicide 
Severity Rating Scale (C-SSRS) and Mini International Neuropsychiatric Inventory 
(MINI). 
• Record prior and concomitant medications. 
• Perform physical examination, including weight and height. 
• Record vital signs (SBP, DBP, orthostatic blood pressure, pulse rate, and oxygen 
saturation). 
• Record a 12-lead ECG. 
• Perform rapid urine pregnancy test for all females of childbearing potential and rapid urine 
pregnancy test on the day of admission to the inpatient unit.  
• Collect blood and urine samples for clinical laboratory tests (hematology, clinical 
chemistry, HIV, 
urinalysis, 
urine 
drug 
screen 
[for 
opioids, 
buprenorphine, 
benzodiazepines, cocaine, amphetamines, and other drugs]), and breath alcohol level 
(BAL). 
• Complete the Timeline Followback (TLFB [i.e., prior use of drug of abuse]) form. 
• COWS Assessment 
• SOWS Assessment 
• Record AEs (after signing the ICF). 
The Screening Visit may be conducted over more than one day; however, all procedures must be 
completed prior to subject randomization and within 30 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.  

 
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10.2 Patient Stabilization Phase Study Day 1 (specific assessments on Study Day 1) 
The assessments on Study Day 1 will include: 
• SOWS Assessment 
• COWS Assessment 
• Naloxone challenge (if COWS <6)  
• Rapid urine pregnancy testing. 
• Vital signs (SBP, DBP, orthostatic blood pressure, pulse rate, and oxygen saturation). 
• Collect urine samples for clinical laboratory tests (urine drug screen [for opioids, 
buprenorphine, benzodiazepines, cocaine, amphetamines, and other drugs,]) and breath 
alcohol level (BAL). 
• Physical examination 
• 12-lead ECG (pre-morning dose of BXCL501-placebo) 
• Record concomitant medication use. 
• Assess and record AEs. 
• ACES Assessment 
• Administration of morphine 
• Administration of placebo film 
• Buccal Assessment for local irritation 
10.3 Patient Stabilization Phase Study Days 2, 3, 4, and 5 (morphine maintenance phase of 
the study) 
The following assessments and procedures performed on all days of the morphine maintenance 
phase of the study will include: 
• Administration of morphine 
• Administration of placebo film 
• SOWS Assessment 
• COWS Assessment 
• ACES Assessment 
• Vital signs (SBP, DBP, orthostatic blood pressure, pulse rate, and oxygen saturation). 
• Urine toxicology 
• 12 lead ECG (pre-morning dose of BXCL501-placebo) 
• Record concomitant medication use. 

 
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• Assess and record AEs. 
Please note that subjects will receive placebo films approximately 12 hours apart during the 
opioid maintenance phase (ie, Days 1-5) to simulate and thus blind treatment with BXCL501 
during Days 6-14. 
10.4 Randomization Study Day 6 
On Study Day 6, subjects will no longer receive oral morphine (30 mg). Subjects in each cohort 
will be randomized to receive either BXCL501 (n=20 subjects) or placebo (n=5 subjects). The 
assessments and procedures on Study Day 6 will include: 
• Review inclusion/exclusion criteria 
• Randomization 
• SOWS Assessment 
• COWS Assessment 
• ACES Assessment 
• Vital signs (SBP, DBP, orthostatic blood pressure, pulse rate, and oxygen saturation). 
• 12 Lead ECG (pre-morning dose) 
• Record concomitant medication use. 
• Assess and record AEs. 
• Rapid urine pregnancy testing 
• Collect blood and urine samples for clinical laboratory tests (hematology, clinical 
chemistry, urinalysis, urine toxicology [for opioids, buprenorphine, benzodiazepines, 
cocaine, amphetamines, and other drugs]) 
• Administration of BXCL501 or Placebo film. 
• Administration of morphine placebo 
• Pharmacokinetics (plasma samples for PK analyses will be collected as listed in the 
schedule of events – Table 2). 
• Buccal Assessment for local irritation 
10.5 Treatment Phase Study Days 7-12 
On Study Days 7 to 12, subjects in each cohort will continue to receive either BXCL501 (n=20) 
or placebo (n=5). The following assessments and data collected will include: 
• SOWS Assessment 
• COWS Assessment 
• ACES Assessment 

 
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• Vital signs (SBP, DBP, orthostatic blood pressure, pulse rate, and oxygen saturation). 
• Urine toxicology 
• 12 Lead ECG (pre-morning dose on Days 8 and 10) 
• Physical Examination (Days 8 and 10) 
• Record concomitant medication use. 
• Assess and record AEs. 
• Administration of BXCL501 or Placebo film. 
• Administration of morphine placebo 
• Pharmacokinetics (plasma samples for PK analyses will be collected as listed in the 
schedule of events at Day 12 – Table 2). 
• Buccal Assessment for local irritation (Day 12) 
10.6 Post Treatment Phase or Early Termination Days 13-14 
On Study Days 13-14, all remaining subjects will receive BXCL501 placebo film and morphine 
placebo.  The following assessments and data collected will include: 
• SOWS Assessment 
• COWS Assessment 
• Record concomitant medication use 
• Assess and record AEs 
• Physical exam including weight (Day 14/discharge)  
• 12 lead ECG (pre-morning dose of BXCL501-placebo) 
• Vital signs (SBP, DBP, orthostatic blood pressure, pulse rate, and oxygen saturation). 
• Buccal Assessment for local irritation (Day 14/discharge) 
• Administration of BXCL501 placebo and morphine placebo 
10.7 Follow-up Period Day 21 (1 week after the end of the study) 
The following assessments and procedures will be conducted 1 week after the end of the study: 
• Record concomitant medication use 
• Assess and record AEs 
• Collect blood and urine samples for clinical laboratory tests (hematology, clinical 
chemistry, urinalysis, urine toxicology [for opioids, buprenorphine, benzodiazepines, 
cocaine, amphetamines, and other drugs]), and breath alcohol level (BAL). 
• Vital signs (SBP, DBP, orthostatic blood pressure, pulse rate, and oxygen saturation). 

 
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• Timeline Followback 

 
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11 STUDY ASSESSMENTS 
11.1 Efficacy 
The effect of study drug will be evaluated using several validated instruments as described 
below. 
11.1.1 Short Opiate Withdrawal Scale of Gossop (also -Gossop) 
The SOWS-Gossop is a 10-item patient reported measure designed to measure the symptoms of 
withdrawal in subjects who are dependent on opioids (Gossop, 1990). Each of the 10 items 
represents a symptom: “Feeling Sick,” “Stomach Cramps,” “Muscle Spasms/Twitching,” 
“Feeling of Coldness,” “Heart Pounding,” “Muscular Tension,” “Aches and Pains,” “Yawning,” 
“Runny Eyes,” and “Insomnia/Problems Sleeping.” Subjects evaluate the severity of each 
symptom over the last 24 hours by selecting either as “None,” “Mild,” “Moderate,” or “Severe.” 
The SOWS-Gossop total score range from 0 to 30, with higher scores indicating greater severity 
of withdrawal symptoms. 
As stated in Section 7.1, SOWS-Gossop is also referred to as SOWS in this document]) 
A sample of the SOWS form is provided in Appendix B. 
11.1.2 Clinical Opiate Withdrawal Scale 
The COWS is an 11-item questionnaire designed to measure a patient’s level of opiate 
withdrawal (Wesson and Ling, 2003). Symptoms evaluated include resting pulse rate, sweating, 
restlessness, pupil size, bone or joint aches, runny nose or tearing, gastrointestinal upset, tremor, 
yawning, anxiety or irritability, and gooseflesh. COWS total scores range from 0 to 48; scores 5 
to 12 are mild, 13 to 24 are moderate, 25 to 36 are moderately severe, and over 36 are severe 
withdrawal. 
The COWS will be administered by an adequately trained professional according to the schedule 
of events. 
A sample of the COWS is provided in Appendix A. 
11.2 Pharmacokinetics 
Blood samples (4 ml) will be collected at 0, 2, 6,  and 12 hours after the first dose of BXCL501 
on Study Days 6 and 12. The 12 hr. sample will be taken just before the administration of the 
next dose of BXCL501 or placebo. 
11.2.1 Sample Collection and Processing 
Details of sample processing will be provided in a separate PK manual. 
11.2.2 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 will be placed in a -70°C (± 12°C) freezer until 
they are shipped to the bioanalytical laboratory. 

 
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11.2.3 Sample Shipping 
• Prior to shipment, the samples will be appropriately packed into a Styrofoam cooler 
containing dry ice. 
• Sufficient dry ice will be added to ensure that the samples will remain frozen for at least 
24 hours for local shipments and for at least 72 hours for remote shipments. 
• Samples will be shipped in two aliquots. The second set will be shipped once the status of 
the first set has been verified.  
• The site staff will maintain an inventory of the samples that are to be shipped to the 
bioanalytical laboratory, including the name of the study drug, protocol number, and the 
subject numbers and samples included in the shipment. A copy of the inventory will 
accompany the frozen PK samples. 
• The samples will be tracked to ensure arrival in a safe and timely manner. 
• Samples will be shipped to: 
 
 
 
 
11.2.4 Analytical Procedures 
11.2.4.1 Bioanalytical Sample Analyses 
A validated liquid chromatography-tandem mass spectrometry procedure will be used to measure 
plasma concentrations of dexmedetomidine. 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. Copies of serially selected 
sample chromatograms for 20% of all samples will be included in the final report. 
11.2.4.2 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. 

 
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11.3 SAFETY 
11.3.1 Adverse Events 
11.3.1.1 Adverse Event Definitions 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with the product. An AE can therefore be any unfavorable and unintended sign 
(including a new, clinically important abnormal laboratory finding), symptom, or disease 
temporally associated with the product, whether or not it is related to the product. 
Preexisting diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition.  Worsening of a 
preexisting condition is considered an AE. 
An expected AE is one for which the nature or severity is consistent with the known AE profile 
of the product.  For an investigational drug, the known information is contained in the 
investigator brochure.  For a marketed drug, the known information is in the current package 
insert. 
An unexpected AE is one for which the specificity or severity is not consistent with the current 
investigator brochure or package insert.  For example, hepatic necrosis would be unexpected 
(greater severity) if the investigator brochure or package insert only listed elevated hepatic 
enzymes or hepatitis.  Likewise, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (greater specificity) if the investigator brochure or package insert only listed cerebral 
vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, 
already documented adverse reaction constitute unexpected AEs.  Examples include acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
and hepatitis with a first occurrence of fulminate hepatitis. 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly 
• Is an important medical event 
Medical and scientific judgment should be used in deciding whether it is appropriate to consider 
other situations serious, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent another of the outcomes listed in the definition previously.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 

 
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emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of a substance use disorder. 
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. 
11.3.1.2 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 the first dose 
of study medication through Day 14 (End of Study) or Early Discontinuation visit and at the 
one week follow up visit. 
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. 
11.3.1.3 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 treatments 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 11.3.1.1) to the medical monitor within 24 hours of first becoming aware of the event 
by telephone.  At the time of first notification, the investigator or designee should provide at a 
minimum the following information if available: 
• Investigator information (name, phone, fax, e-mail). 
• Protocol number. 
• Subject’s study identification and initials. 
• Subject’s date of birth. 
• Date of dose of study drug. 

 
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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, and 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 
(de-challenge) is clinically reasonable. 
11.3.1.3.3 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. 
11.3.1.4 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. 
 
 

 
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11.3.2 Laboratory Safety Assessments 
• 
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Visits and Assessments (Table 2). 
Hematology: 
 
 
Serology: 
Consists of complete blood count (hemoglobin, hematocrit, 
white blood cell count with differential, red blood cell 
count, and platelet count) 
HIV 
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 
Urine drug screen 
Opioids, methadone, fentanyl, buprenorphine, cocaine, 
amphetamine, phencyclidine, and ketamine, 
benzodiazepines, marijuana.  
Breath alcohol level 
Conducted at screening, on Study Day 1, and at the Day 
21/follow up visit.  
11.3.3 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 sitting or supine position for at least 5 minutes at 
the time points specified in the Schedule of Visits and Assessments. Measurements should be 
made at least 1 minute apart using the same arm at each visit. 
At indicated pre-dose and post-dose timepoints, orthostatic measurement of systolic, diastolic 
blood pressure and heart rate will be measured after the subject has been standing for a total of 5 
minutes. Temperature and respiratory rate will be recorded when 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 SBP <90 mmHg, 
DBP <60 mmHg, and pulse <60 bpm. 
11.3.4 Electrocardiogram 
A 12-lead ECG with rhythm strip will be performed at screening, pre-morning dose of 
BXCL501-placebo on study days 1-5, pre-morning dose on study days 6, 8, 10 and pre-morning 
dose of BXCL501-placebo on days 13-14/discharge from the inpatient facility. 

 
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11.3.5 Physical Examination 
A standard physical examination will be performed at screening, study day 1, day 8, day 10, and 
day 14/discharge from the inpatient facility.  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 day 
14/discharge. 
11.3.6 Agitation and Calmness Evaluation Scale 
Overall agitation and sedation will be evaluated with the Agitation-Calmness Evaluation Scale, 
(a single item scale) 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. 
Administration of the ACES will occur at approximately two hours after (-5/+15 min) BXCL501 
or placebo dosing (approximately 10am and 10pm). 
11.3.7 Timeline Follow back 
The Timeline Follow back is a method that can be used as a clinical and research tool to obtain a 
variety of quantitative estimates of marijuana, cigarette, and other drug use. The questionnaire 
will be used in this study (Sobell, 1996). 
The TLFB will be administered by an interviewer, self-administered, or administered by 
computer. It involves asking subjects to retrospectively estimate their drug, marijuana or 
cigarette use 7 days to 2 years prior to the interview date. 
11.3.8 Concomitant Medications 
Concomitant medications will be reviewed and documented during screening, each day during 
the study, and at the follow up visit. 

 
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12 STATISTICAL METHODS 
12.1 General Considerations 
A Statistical Analysis Plan (SAP) that describes the details of the analyses to be conducted will 
be finalized before database lock. 
12.2 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 SOWS 
Score. 
• Per Protocol (PP) Population: All subjects in the ITT Population with no major protocol 
deviations. 
12.3 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 Last Observation Carried 
Forward. 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 SAP, which will be finalized prior to database lock. 
12.3.1 Subject Disposition and Demographic Characteristics 
Subject disposition will include the number of subjects who enroll in the study and the number 
and percentage of subjects included in each analysis population by treatment. The frequency and 
percentage of subjects who withdraw or discontinue from the study, along with the reason for 
withdrawal or discontinuation, will be summarized by treatment. 
Demographics and baseline characteristics, including age, sex, race, weight, height and body 
mass index, will be summarized by treatment for the Safety Population. 
12.3.2 Efficacy Analyses 
12.3.2.1 Primary Efficacy Endpoint 
After the morphine maintenance phase, treatment differences between BXCL501 and placebo on 
peak SOWS scores on Days 6-14 will be analyzed using linear regression or Mixed Model 
Repeated Measures [MMRM]. Treatment differences between BXCL501 and placebo on peak 
SOWS scores on Day 7 (two days after opiate discontinuation) as well as peak SOWS on 
Days 6-14 will be analyzed.  
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. 

 
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12.3.2.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Peak COWS scores during Study Days 6-14. 
• Average COWS scores per day for Days 6-14 (an average will be calculated for each day 
in order to assess time course of withdrawal symptoms). 
• Average SOWS scores per day on Days 6-14 
• Time to dropout after discontinuation of opioid maintenance (Days 6-14). 
• Percentage of subjects dropping out after discontinuation of opioid maintenance within 
each treatment group between Days 6-14. 
• Overall agitation and sedation will be evaluated with the ACES 
Peak COWS scores will be compared between the BXCL501 and placebo groups using linear 
regression or MMRM. Within each group, COWS and SOWS scores will also be compared on 
Days 1-5 and Days 6-14.  
Time to dropout after discontinuation of morphine maintenance will be analyzed using a Cox 
proportional-hazards model. Kaplan-Meier estimates will also be used to generate survival 
curves over time in each treatment group. Logistic regression models will be used to compare the 
BXCL501 and placebo groups on the numbers of participants dropping out after opioid 
discontinuation. 
12.3.3 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. 
The number and percentage of subjects experiencing 1 or more AEs will be summarized by 
treatment, relationship to study drug, and severity. AEs will be coded using Medical Dictionary 
for Regulatory Activities (MedDRA) terminology. Listings of subjects who withdraw from the 
study due to an AE, serious AEs and/or death or lack of treatment effect will be presented. 
Laboratory parameters will be summarized by treatment using descriptive statistics and data 
listings of clinically significant abnormalities. Vital signs and ECG data will be summarized by 
changes from baseline values using descriptive statistics. Chi-square (or Fisher’s exact) tests will 
be used to compare the frequencies of AEs or serious AEs on blood pressure, heart rate, or 
respiratory drive between BXCL501 and placebo, at the beginning of Day 6 and then daily 
during the remainder of this study. 
12.3.4 Pharmacokinetic Analyses 
A separate SAP for the PK analyses will be prepared for the study and will be finalized prior to 
database lock. Data from subjects who participated in the study will be included in the 
pharmacokinetic analysis. Subjects with missing sample concentrations will be included in the 
pharmacokinetic analyses provided their pharmacokinetic parameters can be adequately 
characterized based upon the remaining data. 

 
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12.3.5 Interim Analyses 
The sponsor is planning to conduct one or more interim analyses to evaluate the safety and 
efficacy data to help guide the dosing of BXCL501 for future dose cohorts. 
12.4 Sample Size Determination 
Due to the exploratory nature of this study, BXCL501 effect size estimates remains to be fully 
understood, along with the interpretation of the degree of difference (i.e., threshold of clinical 
importance) between dose conditions (respectively). The proposed sample size of approximately 
225 participants (25 per dosing cohort, 9 cohorts) should be large enough to obtain at least 10 
completers per dosing cohort, ensuring precise 95% confidence intervals on the treatment mean 
difference with a margin of error of <2.7. 

 
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13 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. 
13.1 Sponsor and Investigator Responsibilities 
13.1.1 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. 
13.1.2 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. 
13.2 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: 

 
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1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate informed consent. 
2. All GCP documents have been submitted to and approved by the sponsor or its designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
13.3 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. 
13.3.1 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. 
• Signature Log/Delegation of Study-related Duties. 
• United States Food and Drug Administration 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. 
13.3.2 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. 

 
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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. 
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. 
13.3.3 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 obtained by local labs. A paper copy of 
the laboratory results will be provided to the study site and should be retained with each subject’s 
source data. 
13.4 Data Quality Control 
The sponsor and its designees will perform quality control checks on this clinical study. 
13.4.1 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 

 
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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. 
13.4.2 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. 
13.4.3 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. 
13.5 Study Termination 
The study may be terminated at the sponsor’s discretion at any time and for any reason. 
13.5.1 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. 

 
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13.5.2 Premature Study Termination 
The study may be terminated prematurely for any reason and at any time by the sponsor, IRB, 
regulatory authorities, or the investigator. A decision to prematurely terminate the study is 
binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, the sponsor or designee will notify 
the IRB and regulatory authorities as required. The sponsor or designee must clearly explain the 
reasons for premature termination. 
If the study is terminated prematurely, the investigator 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. 
13.6 Study Site Closure 
At the end of the study, all study sites will be closed for participation. 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. 
13.6.1 Record Retention 
The investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including, but not limited to, those defined by GCP as essential until at least 
2 years after the notification of submission of the final study report to regulatory authorities by 
the sponsor. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent 
to destroy all such material. The sponsor shall have 30 days to respond to the investigator’s 
notice, and the sponsor shall have a further opportunity to retain such materials at the sponsor’s 
expense. 
After completing the study, the sponsor will be provided with the original CRFs or at least a 
legible copy and retain the documents at least 5 years after the completion of the study. 
One copy will remain with the investigator.  The investigator shall arrange for the retention of 
the subject identification codes, subject files, and other source data until at least 5 years after 
notification of submission of the final study report to the regulatory authorities by the sponsor.  
These documents need to be retained for a longer period of time if required by applicable 
regulatory authorities or by agreement with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent 
to destroy all such material. The sponsor shall have 30 days to respond to the investigator’s 

 
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notice, and the sponsor shall have a further opportunity to retain such materials at the sponsor’s 
expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
13.6.2 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.  In addition, identifiable samples can be destroyed at 
any time at the request of the subject. 
13.7 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. 
13.8 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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14 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 clinical study report will be submitted to the appropriate regulatory authorities. 

 
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15 ETHICAL AND LEGAL CONSIDERATIONS 
15.1 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. 
15.2 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. 
15.3 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 APPENDICES 
 

 
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APPENDIX A: CLINICAL OPIATE WITHDRAWAL SCALE (SAMPLE) 
 
 
 

 
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APPENDIX B: SHORT OPIATE WITHDRAWAL SCALE OF GOSSOP (SAMPLE) 
The Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) is a 10-item questionnaire 
developed to evaluate opioid withdrawal symptom severity. The scale was derived from the 
original 32-item Opiate Withdrawal Scale in order to reduce redundancy while providing an 
equally sensitive measure of opioid withdrawal symptom severity appropriate for research and 
clinical practice. In this document, SOWS-Gossop is also referred to as SOWS. 
 
Table 1 is from Gossop, 1990. 

 
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APPENDIX C: AGITATION AND CALMNESS EVALUATION SCALE (SAMPLE)