Clinical trial NCT04283500
Conditions: Opioid-use Disorder
Sponsor: NYU Langone Health
Start date: 2020-11-01; Completion date: 2023-02-25
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Buprenorphine (BUP) is FDA-approved for the treatment of opioid withdrawal and opioid use disorder. Few ED providers have received the necessary DEA registration (aka X waiver) required to prescribe BUP, and urgent appointments to continue ongoing BUP treatment may not be readily available, thus leading to medication discontinuity. A loading dose induction strategy with 32mg of BUP may help effectively link ED patients to outpatient treatment while minimizing known barriers to ED uptake. Administering a "loading dose" of BUP to saturate mu-opioid receptors would extend the duration of action and provide additional time to secure ongoing treatment. Further, BUP's ceiling effect on respiratory depression makes it a remarkably safe drug even at high doses. In recent years, ED providers have begun to incorporate this approach into clinical protocols, however, it has not been formally studied in this clinical setting. The investigator's study represents the necessary step of studying this novel approach in the ED setting to define the parameters for clinical protocols and large-scale studies.

Detailed description:
A novel induction strategy, in which a loading dose of Buprenorphine (BUP) 32mg is administered, has the potential to mitigate barriers to treatment initiation. ED providers can treat patients with BUP for opioid withdrawal since DEA registration (X-waiver) is not required unless they wish to issue a prescription. Current BUP induction protocols, developed for inpatient and ambulatory care settings as well as for unobserved self- administration via prescription, usually recommend a first day dose of 8mg given in divided doses of 2- 4mg. However, patients discharged with ≤ 8mg SL total dose may experience return of withdrawal symptoms and/or opioid craving within only 4 hours.Treatment with a loading dose of 32mg in the ED may provide the necessary bridge treatment, relieving symptoms of withdrawal until a patient is able to attend a follow up appointment for further treatment.

Arms: arm 1: Subjects will be given BUP 32mg in 2 doses, and observed for at least 90 minutes after the 2nd dose. The whole process will take a total of about 3-4 hours including the consenting process. Subjects will be asked questions and be examined repeatedly. Subjects will have 4 in-person visits and a phone call in addition to review of medical records.
Interventions: intervention 1: Buprenorphine Naloxone
Intervention descriptions: intervention 1: Participants will receive the BUP SL 32mg in divided doses rather than all at once. If after the initial 8mg dose a participant experiences over-sedation or another adverse event that would preclude further dosing, such as an allergic reaction, the subsequent dose will not be administered and the patient will be withdrawn from the study. The participant will be reassessed for other possible etiologies for these symptoms.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Buprenorphine Loading in the Emergency Department   
NCT Number: 
NCT04283500 
Study Number: 
19-01700 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
August 1, 2022 
 


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BUPRENORPHINE LOADING IN THE EMERGENCY DEPARTMENT 
(BUP LOAD-ED) 
 
 
Principal Investigator: 
Ryan P. McCormack, MD, MS 
New York University Langone School of Medicine 
Email: Ryan.McCormack@nyulangone.org 
Phone: 212-263-2862 
Additional Investigators: 
Silas Smith, MD 
Clinical Associate Professor, Ronald O. Perelman Department 
of Emergency Medicine 
Email: Silas.Smith@nyulangone.org 
Phone: 212-263-2858 
Stephen Wall, MD 
Associate Professor, Ronald O. Perelman Department of 
Emergency Medicine 
Associate Professor, Department of Population Health 
Email: Stephen.Wall@nyulangone.org 
Phone: 212-562-3346 
 
NYULMC Study Number: 
s19-01700 
Funding Sponsor: 
Emergency Medicine Foundation 
Clinical and Translational Science Institute 
IND/IDE Number: 
N/A 
Study Product: 
Buprenorphine/Naloxone 
Study Product Provider: 
N/A (Bellevue clinical pharmacy as part of usual clinical care) 
ClinicalTrials.gov 
Number 
NCT04283500 
 
Initial version: 11/07/2019 
Amended:  V7 08/01/2022


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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 


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Contents 
STATEMENT OF COMPLIANCE ................................................................................................................. II 
LIST OF ABBREVIATIONS ........................................................................................................................ VI 
PROTOCOL SUMMARY .............................................................................................................................. 7 
1.1.1 
Schedule of Research Events ................................................................................................. 9 
KEY ROLES ............................................................................................................................................... 10 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ..................... 11 
BACKGROUND INFORMATION AND RELEVANT LITERATURE1 ................................................................................................................. 11 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT ......................................................................................... 12 
2.1.1 
Preclinical Data...................................................................................................................... 12 
2.1.2 
Clinical Data to Date .............................................................................................................. 12 
2.1.3 
Study Rationale ..................................................................................................................... 13 
POTENTIAL RISKS & BENEFITS ........................................................................................................................................... 15 
2.1.4 
Known Potential Risks ........................................................................................................... 15 
2.1.5 
Other Risks of Study Participation ........................................................................................ 16 
2.1.6 
Protection Against Overall Risks ........................................................................................... 17 
2.1.7 
Known Potential Benefits ...................................................................................................... 18 
3 
OBJECTIVES AND PURPOSE ......................................................................................................... 19 
3.1 
PRIMARY OBJECTIVE ............................................................................................................................................ 19 
3.2 
SECONDARY OBJECTIVES .................................................................................................................................... 19 
4 
STUDY DESIGN AND ENDPOINTS ................................................................................................. 20 
4.1 
DESCRIPTION OF STUDY DESIGN ....................................................................................................................... 20 
4.2 
DATA COLLECTION AND STUDY MEASURES ..................................................................................................... 20 
4.2.1 
Study Measures .................................................................................................................... 20 
5 
STUDY ENDPOINTS ......................................................................................................................... 22 
5.1.1 
Primary Study Endpoints ....................................................................................................... 22 
5.1.2 
Secondary Study Endpoints .................................................................................................. 23 
5.1.3 
Additional Exploratory Endpoints .......................................................................................... 24 
6 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 24 
6.1 
INCLUSION CRITERIA ............................................................................................................................................. 25 
6.2 
EXCLUSION CRITERIA ........................................................................................................................................... 25 
6.3 
VULNERABLE SUBJECTS ...................................................................................................................................... 25 
6.4 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................................................... 25 
6.4.1 
Use of DataCore/Epic Information for Recruitment Purposes .............................................. 26 
6.5 
DURATION OF STUDY PARTICIPATION ............................................................................................................... 26 
6.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................................ 26 
6.7 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................................. 26 
6.7.1 
Reasons for Withdrawal or Termination ................................................................................ 26 
6.7.2 
Handling of Participant Withdrawals or Termination ............................................................. 27 
6.8 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................................................................ 27 
6.9 
ACQUISITION .......................................................................................................................................................... 27 
6.9.1 
Formulation, Appearance, Packaging, and Labeling ............................................................ 27 
6.9.2 
Product Storage and Stability ................................................................................................ 28 
6.9.3 
Preparation ............................................................................................................................ 28 
6.9.4 
Dosing and Administration .................................................................................................... 28 
6.9.5 
Route of Administration ......................................................................................................... 28 


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6.9.6 
Starting Dose and Dose Escalation Schedule ...................................................................... 28 
6.9.7 
Dose Adjustments/Modifications/Delays ............................................................................... 28 
6.9.8 
Duration of Therapy ............................................................................................................... 29 
6.9.9 
Tracking of Dose ................................................................................................................... 29 
6.9.10 
Study Agent Accountability Procedures ............................................................................ 29 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................................... 29 
7.1 
STUDY SPECIFIC PROCEDURES ......................................................................................................................... 29 
7.2 
STANDARD OF CARE STUDY PROCEDURES ..................................................................................................... 29 
7.3 
LABORATORY PROCEDURES/EVALUATIONS ..................................................................................................... 30 
7.3.1 
Clinical Laboratory Evaluations ............................................................................................. 30 
7.4 
STUDY SCHEDULE ................................................................................................................................................. 30 
7.4.1 
Screening .............................................................................................................................. 30 
7.4.2 
Enrollment/Baseline .............................................................................................................. 30 
7.4.3 
Intermediate Research Visits ................................................................................................ 30 
7.4.4 
Final Study Visit (Phone) ....................................................................................................... 31 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................................... 31 
7.5.1 
Precautionary Medications, Treatments, and Procedures .................................................... 31 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................................... 31 
7.7 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES .......................................................................... 31 
8 
ASSESSMENT OF SAFETY ............................................................................................................. 32 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ........................................................................................................ 32 
8.1.1 
Definition of Adverse Events (AE) ......................................................................................... 32 
8.1.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 32 
8.1.3 
Definition of Unanticipated Problems (UP)............................................................................ 32 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ......................................................................................................... 32 
8.2.1 
Severity of Event ................................................................................................................... 32 
8.2.2 
Relationship to Study Agent .................................................................................................. 33 
8.2.3 
Expectedness ........................................................................................................................ 33 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ........................................... 33 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 34 
8.4.1 
Adverse Event Reporting ...................................................................................................... 34 
8.4.2 
Serious Adverse Event Reporting ......................................................................................... 34 
8.4.3 
Unanticipated Problem Reporting ......................................................................................... 34 
8.4.4 
Reporting of Pregnancy ......................................................................................................... 34 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ................................................................. 35 
8.6 
STUDY HALTING RULES ....................................................................................................................................... 35 
8.7 
SAFETY OVERSIGHT ............................................................................................................................................. 35 
9 
CLINICAL MONITORING .................................................................................................................. 35 
10 
STATISTICAL CONSIDERATIONS .................................................................................................. 36 
10.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................................. 36 
10.2 
MEASURES TO MINIMIZE BIAS ............................................................................................................................. 36 
10.2.1 
Enrollment/Randomization/Masking Procedures .............................................................. 36 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 36 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 36 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 37 
13.1 
ETHICAL STANDARD .............................................................................................................................................. 37 
13.2 
INSTITUTIONAL REVIEW BOARD .......................................................................................................................... 37 
13.2.1 
Consent/Assent and Other Informational Documents Provided to Participants ............... 37 
13.2.2 
Consent Procedures and Documentation ......................................................................... 37 


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13.3 
INFORMED CONSENT PROCESS ......................................................................................................................... 38 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............... 38 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY ...................................................................................................... 38 
13.4.1 
Research Use of Stored Human Samples, Specimens, or Data ...................................... 38 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................... 39 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................................................... 39 
14.2 
STUDY RECORDS RETENTION ............................................................................................................................ 39 
14.3 
PROTOCOL DEVIATIONS ....................................................................................................................................... 39 
14.4 
PUBLICATION AND DATA SHARING POLICY ....................................................................................................... 40 
15 
STUDY FINANCES ............................................................................................................................ 40 
15.1 
FUNDING SOURCE ................................................................................................................................................. 40 
15.2 
COSTS TO THE PARTICIPANT ............................................................................................................................... 40 
15.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................................ 41 
16 
STUDY ADMINISTRATION ............................................................................................................... 41 
16.1 
STUDY LEADERSHIP .............................................................................................................................................. 41 
17 
CONFLICT OF INTEREST ................................................................................................................ 41 
18 
REFERENCES ................................................................................................................................... 42 


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List of Abbreviations 
 
 
AE 
Adverse Event/Adverse Experience 
BUP 
Buprenorphine 
BUP/NX 
Buprenorphine/Naloxone 
CFR 
Code of Federal Regulations 
COWS 
Clinical Opioid Withdrawal Scale 
CRF 
Case Report Form 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DEA 
Drug Enforcement Administration 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual 
ED 
Emergency Department 
EQ-5D-3L 
EuroQol 5 dimensions, 3rd level 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
LFTs 
Liver function tests (AST, ALT) 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NIH 
National Institutes of Health 
NYULH 
New York University Langone Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
US 
United States 


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Protocol Summary 
 
Title 
Buprenorphine Loading in the Emergency Department 
Short Title 
BUP LOAD-ED 
Brief Summary 
Buprenorphine (BUP) is FDA-approved for the treatment of opioid withdrawal 
and opioid use disorder. Prior studies have demonstrated feasibility, safety, 
and efficacy of Emergency Department (ED)-initiated BUP, but there are 
many barriers to widespread implementation of this intervention. Few ED 
providers have received the necessary DEA registration (aka X-waiver) 
required to prescribe BUP, and urgent appointments to continue ongoing 
BUP treatment may not be readily available, thus leading to medication 
discontinuity. A loading dose induction strategy with 32mg of BUP may help 
effectively link ED patients to outpatient treatment while minimizing known 
barriers to ED uptake. Administering a loading dose of BUP to saturate mu- 
opioid receptors would extend the duration of action, therefore providing 
additional time to secure ongoing treatment. Further, BUP’s ceiling effect on 
respiratory depression makes it a remarkably safe drug even at high doses. 
In recent years, ED providers have begun to incorporate this approach into 
clinical protocols; however, it has not been formally studied in this clinical 
setting. Our study represents the necessary step of studying this novel 
approach in the ED setting to define the parameters for clinical protocols and 
large-scale studies. 
Phase 
Phase IV 
Objectives 
1. 
To evaluate the feasibility, acceptability, safety and utility of a BUP 
32mg sublingual (SL) loading dose induction strategy in the ED. 
2. 
To determine optimal processes for an ED protocol and clinical trial. 
Methodology 
This is an open-label, single arm study in which 35 ED patient-participants 
who have untreated moderate to severe opioid use disorder (OUD) and are 
experiencing opioid withdrawal will receive treatment with BUP 32mg SL 
along with referral for ongoing treatment. Assessments will occur in-person 
on days 0-3 and by phone on day 30, to assess the feasibility, acceptability, 
safety, and utility of this clinical intervention primarily by assessing its effect 
and the duration of effect on opioid withdrawal, craving, and sedation as well 
as evaluating engagement in ongoing treatment. 
Endpoint 
For the primary and secondary objectives, standardized and validated 
instruments will be used to measure the following: opioid and other illicit drug 
use using the timeline follow back method and urine or saliva drug screen 
(UDS); opioid withdrawal and craving using objective and subjective opioid 
withdrawal scales (e.g. COWS and SOWS) and visual analogue scales 
(VAS); level of awareness/sedation using the Richmond Agitation Sedation 
Scale (RASS), patient reported outcomes of quality of life and functional 
status using the PROMIS Global 10 and Treatment Effectiveness 
Assessment (TEA); healthcare utilization using the non-study treatment 
service use form, participant satisfaction and perceived utility of ED-initiated 
intervention. Engagement in treatment will be assessed by self-report and/or 
confirmed by treatment provider. An adverse event log will be maintained. 
Study Duration 
Duration: 7-10 months 
Participant Duration 
1 month 


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Population 
Eligible participants will be recruited from the Bellevue Hospital ED and 
NYULH EDs, which have a large proportion of patients with opioid use 
disorder (OUD), among other substance use disorders (SUD). Individuals 
can be selected to participate if they are 18 years and older, speak English, 
meet DSM-5 criteria for moderate to severe OUD, have used opioids within 7 
days, have not used  methadone at a dose greater than 30mg within 72 
hours or 10mg within 24hours, have objective signs of opioid withdrawal with 
a COWS score ≥8 or are expected to have a score of this level during their 
ED visit, are willing and able to participate, and have adequate locator 
information including access to a phone. Patients will be excluded if they are 
currently engaged in medication treatment for OUD (methadone, BUP, or 
naltrexone), are prescribed opioids for treatment of pain, cognitively impaired, 
in police custody, have an allergy to BUP, receive a dose of BUP greater 
than 8mg before study enrollment, or have acute medical or psychiatric 
conditions or co- occurring substance use disorders that are deemed to 
preclude safe participation, such as recent methadone use. Subjects will also 
be excluded if they do not have reliable access to a phone or if a 3-hour 
observation period in the ED is not feasible (may be limited by provider or 
patient availability). 
Study Sites 
The study will take place in the Emergency Departments at Bellevue 
Hospital and NYU Langone Health sites including NYULH-Tisch, NYULH-
Brooklyn, NYULH-Winthrop, and NYULH-Cobble Hill.  
Number of participants 
35 participants 
Description of Study 
Agent/Procedure 
BUP 32 mg SL (in two doses of 8mg and 24mg) 
Key Procedures 
Urine or saliva test, administration of BUP 32 mg SL. 
Statistical Analysis 
Statistical analyses will consist of descriptive analyses and will provide 
summary tabulations and measures of central tendency, variance, and other 
distributional properties of the obtained results. Where applicable, we will also 
conduct cross-tabulations and comparative analyses of variance based on 
selected key characteristics of the study participants (e.g., sex, age 
categories, withdrawal scores at baseline). 


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1.1.1 
Schedule of Research Events 
 
 
Research Visits 
Index Day 1 Day 2 Day 3 Day 
30 
Eligibility and Enrollment 
Potential participants identified by staff referral and/or research staff 
screening  
x 
Approval of clinical provider (confirmation that medically and 
psychiatrically stable and appropriate for study participation) 
x 
Written Informed Consent and Medical Release 
x 
Eligibility Assessments and Checklist (DSM-5 OUD, Medical exam, 
COWS)* 
x 
Assessments 
Demographics (PhenX) 
x 
 
 
 
 
Drug Use Inventory and other Substance Use Measures (PhenX, 
TLFB) 
x 
x 
x 
x 
x 
Urine and/or Saliva Toxicology (Standard panel, BUP, FEN) 
x 
 
 
 
 
Withdrawal and Craving Measures (COWS, SOWS, scales)* 
x 
x 
x 
x 
x 
Quality of life and treatment (PROMIS-GLOBAL-10, TEA) 
x 
x 
x 
x 
x 
Overdose and risk assessments 
x 
x 
x 
x 
x 
Qualitative Assessments/Participant Satisfaction 
x 
x 
x 
x 
x 
Non-Study Medical and Other Services (NMS) 
x 
x 
x 
x 
x 
Adverse Events 
x 
x 
x 
x 
x 
Administrative Actions and Review  
Appointment scheduling for research visits and follow up care 
x 
x 
x 
x 
 
Participant compensation (value) 
80 
40 
40 
40 
40 
Round Trip Metrocard 
x 
x 
x 
x 
Healthcare Utilization Review 
x 
x 
x 
 
*Multiple assessments conducted before BUP dose 1, after BUP dose 1, and after BUP dose 2 


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Key Roles 
 
Principal Investigator: 
Ryan P. McCormack, MD, MS 
New York University Langone School of Medicine 
Email: Ryan.McCormack@nyulangone.org 
Phone: 212-263-2862 
 
Additional Investigators: 
Silas Smith, MD 
Clinical Associate Professor, Ronald O. Perelman Department of Emergency Medicine 
Email: Silas.Smith@nyulangone.org 
Phone: 212-263-2858 
 
Stephen Wall, MD 
Associate Professor, Ronald O. Perelman Department of Emergency Medicine 
Associate Professor, Department of Population Health 
Email: Stephen.Wall@nyulangone.org 
Phone: 212-562-3346 
 
 
Study Management: 
 
Soo-Min Shin, MA 
Senior Research Project Manager 
Email: Soo-Min.Shin@nyulangone.org 
Phone: 646-501-4038 
 
Heather Anderson, MS 
Project Manager 
Email: Heather.anderson@nyulangone.org 
Phone: 646-501-0125 


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2 Introduction, Background Information and Scientific Rationale 
 
Background Information and Relevant Literature1 
 
Effective treatments to reduce morbidity and mortality associated with opioid use disorder (OUD) are known, 
yet few individuals are provided access to these treatments2. Narrowing the treatment gap by expanding 
access to treatment beyond specialized drug treatment settings is a widely accepted public health priority. 
For many reasons, the Emergency Department (ED) is a logical point of intervention: 1) There is a 
disproportionately high and growing prevalence of OUD among ED patients; ED visits associated with 
opioids doubled between 2004 and 2014, and visits for opioid overdose increased by approximately 30% 
from July 2016 through September 20173-6 ; 2) Both multiple ED visits and surviving an overdose are strong 
predictors for subsequent overdoses and even death7,8 ; 3) For many individuals, the ED is the primary or 
only access point in the healthcare system, and, therefore, treatment,4,5 4) The ED visit may represent a 
critical, time-sensitive moment of motivation for treatment. This context provides a unique opportunity for 
interventions addressing OUD to gain entry into the ED; however, there is a need to translate treatment 
approaches to interventions that are feasible and effective in the ED setting. 
 
The landmark trial conducted by D'Onofrio et al. demonstrated the feasibility, safety, and efficacy of ED- 
initiated buprenorphine (BUP) in the Yale-New Haven Hospital ED9. Despite this success, few EDs have 
adopted this intervention. ED providers often cite time and resource limitations10. Widespread 
implementation is difficult, as few ED providers have received the necessary DEA registration (aka X- 
waiver) required to prescribe BUP and appointments for linkage to ongoing care within 24 hours may not 
be readily available. Even in an optimized system, other factors such as problems with medication pre- 
authorization may delay access. Thus, a critical barrier to ED-initiated BUP is ensuring patients have access 
to ongoing treatment with BUP without medication discontinuity. 
 
A novel induction strategy, in which a loading dose of Buprenorphine (BUP) 32mg is administered, 
has the potential to mitigate this barrier. ED providers can treat patients with BUP for opioid withdrawal 
since DEA registration (X-waiver) is not required unless they wish to issue a prescription. Current BUP 
induction protocols, developed for inpatient and ambulatory care settings as well as for unobserved self- 
administration via prescription, usually recommend a first day dose of 8mg given in divided doses of 2- 
4mg.11 However, patients discharged with ≤ 8mg SL total dose may experience return of withdrawal 
symptoms and/or opioid craving within only 4 hours.12,13 Treatment with a loading dose of 32mg in the ED 
may provide the necessary bridge treatment, relieving symptoms of withdrawal until a patient is able to 
attend a follow up appointment for further treatment. 
 
Translating existing strategies by taking advantage of the unique and well-established pharmacological 
properties of BUP has the potential to alleviate the aforementioned barriers to ED-initiated BUP. 
Demonstrating that this efficacious pharmacotherapy can be initiated practically in the ED as a bridge to 
ongoing BUP treatment would support efforts to expand the delivery and impact of evidence-based opioid 
treatment. Further assessment is needed to define the clinical parameters for this induction strategy before 
incorporating it into clinical protocols and large-scale studies. Our proposal represents the necessary first 
step in studying this novel approach in the ED setting. 


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Name and Description of the Investigational Agent 
 
Buprenorphine (BUP) is a lipophilic thebaine derivative with a high binding affinity at the mu-opioid 
receptor where it has partial agonist effects and at the kappa opioid receptor where it is a competitive 
antagonist. Like many opioids, BUP was initially commercially developed as an analgesic14. In October 
2002, the FDA approved BUP for detoxification and maintenance treatment of opioid dependence. For 
these indications BUP is marketed as Subutex® (Reckitt Benckiser), and in a 4:1 ratio combination with 
naloxone (BUP-NX), as Suboxone® (Reckitt Benckiser). The BUP-NX combination was developed to limit 
abuse liability and diversion13,15-18. Generic formulations of BUP-NX are now available. Recently Reckitt 
Benckiser began marketing a sublingual BUP-NX film. In this document, we refer to BUP-NX as either 
BUP-NX or BUP. All study participants will be treated with BUP-NX formulations, though this document 
may refer to the study drug as simply “BUP”. 
 
BUP was first proposed as an alternative to methadone for treatment of opioid dependence in 1978 and 
has been studied extensively since. As reported by Jasinski, Mello, and Mendelson, buprenorphine has a 
low physical abuse potential and a high potential to substitute for heroin and reduce heroin self- 
administration.19-22 These clinical studies suggested that BUP could be used safely and effectively used 
for pharmacotherapy in clinical settings, but formal approval for clinical use required systematic data on 
safety and efficacy of BUP when used in larger groups. A set of clinical trials were designed to evaluate 
the utility from a medication development perspective, and subsequent trials, compared buprenorphine to 
methadone; evaluated dose comparisons using dose response; and compared buprenorphine to 
placebo.14,19,22-28 
 
Numerous clinical trials involving thousands of participants, have overwhelmingly established both the 
efficacy and effectiveness of BUP-NX in the community.18,22,24,29-36 BUP and BUP-NX are safe and 
effective alternatives to methadone20,37-41 and enable significant and substantial improvement over time in 
psychosocial functioning.42 
 
Maximal drug effects typically occur at approximately 8 to 16 mg, although sublingual daily doses up to 32 
mg have been safely administered for a period of up to a year.20,43,44 Variability in individual dosing 
addresses the range and severity of opioid dependence across patients. Because of BUP’s lipophilicity 
and high affinity to the mu-opioid receptor, less-frequent-than-daily dosing is possible for some 
patients.45 BUP’s slow dissociation from mu-opioid receptors contributes to its long duration of action and 
smooth day-to-day course, and minimizes symptoms and signs of withdrawal upon cessation.46,47 
 
Prescribing and Safety: Details on BUP-NX (Suboxone®) prescribing, pharmacokinetics and 
pharmacodynamics, metabolism and elimination, safety and toxicity are described in the Suboxone 
package insert submitted with this protocol. 
 
2.1.1 Preclinical Data 
 
See package insert. 
 
2.1.2 Clinical Data to Date 
 
A small handful of studies to date have demonstrated the safety and effectiveness of high dose BUP 
induction, ranging from case reports to randomized controlled trials. Ang-Lee et al. observed a significant 
mean reduction in Clinical Opioid Withdrawal Scale (COWS) score in heroin-dependent patients using 24 
mg SL BUP. Furthermore, participants in this small open-label study did not experience any significant 
adverse events, aside from one participant who had precipitated withdrawal which resolved within 4 
hours, and withdrawal suppression lasted >72 hours.48 A similar study by Kutz et al. treated 10 heroin-
users in acute withdrawal with 32 mg BUP (8mg every 5 minutes for 20 minutes), and reported that nine 
of the participants completed detoxification with negligible withdrawal symptoms, with suppression also 
lasting > 3- 4 days. Again, no adverse events were reported.39 


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Within the past two years, four randomized controlled trials out of Iran49-52 have provided evidence that 
high dose BUP for opioid withdrawal is both safe and reduces craving/withdrawal over an 
extended time frame following initial administration. One of these studies randomized 90 opioid- 
dependent men in withdrawal to three groups to receive single doses of 32 mg, 64 mg, and 96 mg 
respectively. They observed a significant reduction in craving symptoms using a Visual Analogue Scale 
(VAS) in all three cohorts that was more pronounced at 64 mg than 32 mg, but no greater effect was 
observed at 96 mg. The resolution of craving was maintained at 5 days post initial treatment. Only four 
participants developed side effects, which included hypotension, nausea and vomiting (expected side 
effects of BUP even at low doses), all of which resolved with hydration and anti-emetics49. This research 
group also published a recent case report of heroin detoxification using 120 mg SL BUP in a single 
patient experiencing severe withdrawal. Withdrawal suppression persisted for 4 days after initial 
administration, and the patient was discharged without need for additional buprenorphine. There were no 
side effects or adverse events reported in this case. 
 
Of note, the other studies out of Iran specifically investigated the effectiveness of single, high dose 
buprenorphine in mitigating suicidal ideation/depressive symptoms in patient with concurrent opioid use 
disorder during withdrawal. Nonetheless, they provide support for its safety in single high doses at 
initiation51,52. 
 
2.1.3 Study Rationale 
 
 
Study Rationale and Dose Rationale 
 
Under most current BUP induction guidelines, only a partial induction is feasible during a brief ED visit, 
where 8mg is given in divided doses of 2-4mg.11 Thereafter, a maintenance dose is reached ranging from 
16 to 32mg, but this is not currently achieved during ED visits. The threshold for suppressing withdrawal 
and the rewarding effects of an opioid challenge occurs when greater than 70% of µ-opioid receptors are 
occupied, which typically occurs at plasma BUP concentrations of ≥ 2ng/mL53. Patients discharged after 
administration of ≤8mg SL BUP may have both incompletely treated acute withdrawal symptoms and 
return of opioid craving within only 4 hours.9 Thus, a patient would need to successfully navigate a 
complex medical system to obtain BUP for continued unobserved induction – and would have return of 
withdrawal and craving if not done within a certain period of hours. In real-world settings, without the 
heavily supported conditions present in the published trials, high rates of failure to engage in treatment 
after ED discharge have been observed.16,9,17 
 
Administration of a larger 32mg SL BUP dose during the ED visit may improve engagement in OUD 
treatment by producing both a greater reduction in opioid withdrawal intensity during the ED stay and 
prolonged suppression of opioid craving after discharge. A rapid ED induction eliminates the need for an 
unobserved induction after discharge, which relies on immediate access to prescribed buprenorphine and 
patient compliance with complex titration instructions.12,13,53 Current data suggest both fewer acute 
withdrawal symptoms and increased duration of effect with BUP doses ≥8mg SL. Among heroin- 
dependent patients presenting with acute withdrawal treated with 8mg SL BUP, Oreskovich et al. 
observed a mean reduction in Clinical Opioid Withdrawal Scale (COWS) score from 15 to 8.54 In a similar 
population, using 24mg SL BUP, Ang-Lee et al. observed a much larger mean reduction in COWS from 
17 to 2 with withdrawal suppression lasting >72 hours.6 Whitley et al. found that compared to higher 
doses, a low initial dose of BUP (2mg SL) was associated with increased rates of protracted withdrawal 
and treatment failure.7 
 
In a 2014 meta-analysis, Mattick et al. showed that buprenorphine is superior to placebo in retaining 
people in treatment, but only at higher doses (16 mg or more), and not at low or medium doses (15 mg or 
less), based on objective urinalysis results.55 The authors of studies included this meta-analysis 
suggested that a possible explanation for poorer retention in BUP maintenance treatment may have been 
too-slow induction onto buprenorphine. Given the relative safety of buprenorphine, it may be possible to 


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induct people to higher doses at a more rapid rate and thus overcome the problem of slightly poorer 
retention for buprenorphine compared with methadone.56,57 Researchers have also suggested that, by 
nature of buprenorphine’s different pharmacological properties, it may have advantages in some settings 
and under some policies where its relative safety and alternate-day administration are useful clinically 
compared to methadone. 
 
For these and other aforementioned reasons, more practical alternative models have been proposed for 
ED settings. Specifically, the rapid induction method proposed in this study is already used widely 
across the state of California (as well as other regions) through the statewide SAMHSA-funded ED- 
BRIDGE program; the protocol is published on the ED-BRIDGE website and endorsed by ACEP and 
California Society of Addiction Medicine (CSAM). Thus, in this study, we wish to formally study an 
induction procedure that is already in clinical use. Also, it has been studied on a limited scale in 
controlled research settings conducted outside the ED. Existing data suggests this approach is feasible, 
acceptable, safe, and successful in effectively extending the duration of effect of BUP (Section 2.1.2 
Clinical Data to Date). 
 
In ED patients, return of withdrawal symptoms and opioid craving during the high-risk period after 
discharge but before formal linkage to care likely promotes early return to illicit opioid use and failure to 
engage in OUD treatment.13 A SL dose of 4mg achieves a plasma BUP concentration sufficient to 
suppress craving and withdrawal for ≤2 hours; a SL dose of 8mg provides ≤ 4 hours of therapeutic 
effect.13,53 A 32mg SL dose of BUP may provide effective treatment for over 24 hours or more. The 
dosage of BUP SL 32mg being used in this study has been approved by the FDA for the treatment of 
OUD for daily use in the maintenance phase. 
 
ED-initiated BUP induction dosing potentially influences patient satisfaction and retention in opioid use 
disorder (OUD) treatment after discharge. Translating existing BUP induction and treatment strategies by 
taking advantage of the unique and well-established pharmacological properties of BUP has the potential 
to mitigate the aforementioned barriers to ED-initiated BUP. This study aims to evaluate the feasibility, 
acceptability, safety, and utility of the rapid loading induction strategy in the ED. Demonstrating that this 
efficacious pharmacotherapy can be initiated practically in the ED as a bridge to ongoing BUP treatment 
would support the efforts to expand the delivery and impact of evidence-based opioid treatment. We 
hypothesize that enrollment of 35 ED patients with OUD and opioid withdrawal in an open-label, single 
arm study of a BUP 32mg loading dose induction will provide necessary information on feasibility, utility, 
and identification of optimal processes for the development of a treatment initiation protocol suitable for 
the ED setting so that we can properly plan subsequent large-scale clinical trials. 
 
Safety 
 
Owing to its partial opioid agonist properties, BUP has limited respiratory depressant effects, low toxicity 
even at high doses, and limited risk of overdose. The closely monitored ED setting used in this study, in 
addition to BUP’s ceiling effect on respiratory depression and sedation, makes it a remarkably safe drug, 
even at high doses.39,58 At sufficient doses, BUP blocks the effects of exogenous opioids and can both 
reduce illicit use and afford some level of protection against overdose. Chart review of 94 ED patients at 
Highland Hospital who received 24-32mg SL BUP suggests this approach is feasible and safe—no cases 
of clinically significant sedation, precipitated withdrawal, or other adverse event were observed. Studies 
described in Section 2.1.2 (Ang-Lee, Kutz, and Ahmadi), have provided further evidence that this dosage 
is both safe and effective when administered in the ED setting. 
 
BUP has abuse potential, though limited in contrast to full agonists like methadone.37,40-42,44-47,59 Although 
there is a ceiling on BUP’s respiratory depressant effects,37 interactions with other CNS depressants, 
such as benzodiazepines and alcohol, are potentially dangerous,60,61 and patients should be cautioned to 
avoid acute binge use of CNS depressants.62 Because BUP is metabolized by cytochrome P-450 3A4,63 
drugs that inhibit or induce this system can affect BUP levels. Known inhibitors include erythromycin, 
ketoconazole, grapefruit juice and certain HIV protease inhibitors63 which may increase BUP levels. 
Inducers include phenobarbital, carbamazepine, and phenytoin which could reduce BUP levels and lead 
to withdrawal symptoms, 62 though this has not been observed clinically. 


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The primary objective of this study is to provide further evidence for the safety, utility, and feasibility of a 32 
mg initiating does of buprenorphine. While this dose has been approved for maintenance treatment, the 
FDA label recommends a lower dose for the first day of initial induction, specifically “an induction dosage of 
up to 8 mg/2 mg SUBOXONE sublingual film is recommended. Clinicians should start with an initial dose of 
2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate upwards in 2 or 4 mg increments of 
buprenorphine, at approximately 2-hour intervals, under supervision, to 8 mg/2 mg buprenorphine/naloxone 
based on the control of acute withdrawal symptoms.”64 We expect that this study will further support existing 
evidence that 32 mg dose of BUP is not only safe to administer, but will extend withdrawal suppression and 
facilitate linkage to care for patients with OUD. 
 
Potential Risks & Benefits 
 
2.1.4 Known Potential Risks 
Medication Risks: Participants in this study will be treated with the BUP-Naloxone (BUP-NX) formulation 
currently in stock at Bellevue pharmacy, which is the BUP-X sublingual (SL) tablet. The package insert for 
Suboxone (BUP-NX sublingual) serves as the primary source of risk information. BUP SL is FDA- 
approved in tablet and film formulations as BUP-NX and as the BUP monoproduct (no naloxone) for the 
treatment of OUD. Naloxone is for abuse deterrence and is inactive when taken as prescribed (due to 
negligible absorption and metabolism through the hepatic first pass effect). The formulations have 
comparable indications, dosing, bioactivity, and risks. If the medication on formulary at Bellevue is 
different than BUP-NX tablet, the risks will be approximately identical. 
 
The FDA label prescribing information states “an induction dosage of up to 8 mg/2 mg SUBOXONE 
sublingual film is recommended. Clinicians should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg 
BUP-NX and may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour 
intervals, under supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute 
withdrawal symptoms.”64 The dosage of BUP SL 32mg being used in this study exceeds this 
recommendation for the initial dose; it is, however, within the dose range approved for the daily 
maintenance phase (i.e., for continuation after the first day(s) of induction). No toxicity or long-term risks 
beyond those described in the prescribing instructions are expected. A medical screen will be performed 
in accordance with prescribing guidelines. As described in Section 2.1, the case review of 94 ED patients 
at Highland Hospital who received 24-32mg BUP SL and other published studies conducted in other 
clinical and research settings – as well as the unique pharmacological properties of BUP’s ceiling effect 
on sedation– suggests this approach is feasible and safe. 
 
The purpose of this study is NOT to amend the product labeling. 
 
Two known risks of BUP are that it may cause over-sedation (particularly among individuals with certain 
medical problems or concomitant sedative use) and precipitated withdrawal (when BUP is taken too 
soon after full opioid agonist use, particularly methadone, before the individual is in sufficient opioid 
withdrawal). The higher dosing may have increased potential to cause over-sedation; it is less likely to 
increase the risk of precipitated withdrawal. In fact, worsening withdrawal is often treated by administering 
higher doses of BUP, including in the clinical protocol for the Bellevue Hospital ED (which recommends 
up to the dose being tested in this study).  Given the pharmacology of BUP, the onset of these events 
would be expected within 30 to 90 minutes of receipt of the medication. During this time, all participants 
will remain monitored in the ED clinical research setting where there is capacity to address these issues 
should they arise. Management of over-sedation and withdrawal are within the scope of general ED 
practice; the principal investigator is a practicing ED clinician and has a wealth of expertise and 
experience in addressing these problems. We will have safety plans in our operating procedures and 
activate these plans should events occur. 
 
The risks of over-sedation and precipitated withdrawal will be mitigated by rigorous patient selection 
criteria and research procedures and assessments. Prior to receiving any BUP, potential participants will 
be screened for co-occurring substance use and medical problems that would predispose them to over- 
sedation, and they will be screened for recent use of methadone or other long-acting opioid agonists and 
will have a formal assessment of opioid withdrawal severity to minimize the risk of precipitated withdrawal. 
For this reason, patients who have used methadone at a dose that is greater than 30mg within 72 hours 


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or greater than 10mg within 24 hours or at an unknown dose (e.g., obtained illicitly) will be ineligible for 
study participation. 
 
Active use of opioids (within 7 days) will be confirmed by a positive toxicology test and/or by the clinical 
assessment by the study clinician or ED provider (e.g., self-report plus documented history of opioid use 
and objective findings consistent with opioid withdrawal). We will not rely on toxicology testing alone as 
synthetic and semi-synthetic opioids are not reliably detected for up to 7 days using currently available 
CLIA-waived, rapid toxicology tests.  The use of urine and/or saliva toxicology tests that are not CLIA-
waived will be for non-clinical, research purposes. 
 
Participants will receive the BUP SL 32mg in divided doses, rather than all at once. If after an initial dose 
of BUP ≤8mg SL, a participant experiences over-sedation or another adverse event that would preclude 
further dosing, such as an allergic reaction, the subsequent dose will not be administered and the patient 
will be withdrawn from the study. The participant will be reassessed for other possible etiologies for these 
symptoms (for example, infection can cause sedation or mimic withdrawal). Precipitated withdrawal, 
however, would not necessarily preclude subsequent BUP dosing. In most cases, the treatment for 
precipitated withdrawal is to administer additional BUP in higher doses. In other words, the latter BUP 
24mg dose would be the treatment for precipitated withdrawal in most cases. The determination of 
whether a participant who is experiencing apparent precipitated withdrawal should receive additional BUP 
will be determined on a case-by-case basis at the discretion of the study clinician. 
 
 
2.1.5 Other Risks of Study Participation 
 
Confidentiality: Risks to participants include possible loss of confidentiality/privacy pertaining to their 
protected health information. Participants will be asked to provide sensitive information, including drug 
use. 
 
The PI and study staff have completed requisite IRB Human Subjects and HIPAA trainings. Any future 
staff will have completed requisite IRB Human Subjects and HIPAA trainings. The PI will provide any 
future staff with training in their responsibilities for maintaining participant confidentiality. 
 
The PI will apply for a Federal Certificate of Confidentiality to encompass protocol activity and participant 
data and ensure against the release of confidential information. Research records apart from clinical 
assessments will be distinct from the medical record to help ensure the protections of the Certificate of 
Confidentiality. 
 
EMR documentation will be similar for patients being treated for OUD whether or not they participate in 
the study. ED-initiated BUP is currently offered as first line treatment for OUD in the Bellevue ED to 
patients who are clinically appropriate to receive it. As per standard clinical care and usual practice, 
when BUP is initiated in the ED to a patient, the related elements of clinical care are documented in the 
EMR (e.g., diagnosis, assessments, medication administered, response to treatment, and referral 
information). Specific assessments and actions conducted by the study staff that are directly related to 
clinical care may be made available to the clinical staff and/or entered into the EMR to ensure accurate 
clinical documentation and closed-loop communication and safety. Specifically, elements that may be 
communicated may include vital signs, state of opioid withdrawal, craving, or sedation, details of last 
opioid use (frequency, timing, type, route), acute adverse events, follow-up appointment information, and 
drug administration and prescribing record. There will be no mention of the research-only assessments 
(e.g., legal and social problems, healthcare utilization, quality of life, satisfaction, etc.) or inclusion of the 
data resulting from them in the EMR; these data will only be entered into the research record (using a 
unique identifier). 
 
All research data will be entered into NYU-internal REDCap surveys administered on tablets and/or PCs 
using Bellevue’s and NYULH’s secure networks for any data containing participant protected health 
information. The tablet devices have security protections that are HIPAA compliant. Hard copy Case 
Report Forms will be used if necessary and all data from paper forms will be copied into REDCap as soon 
as possible. Data will be stored on secure servers and/or in locked filing cabinets in my locked research 
office with only authorized study personnel as identified by the principal investigator and project manager 
for this study having access. Unique identifiers will be used to identify participants in the password- 
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findings will utilize only aggregate data and no publication or presentation will involve any use of 
individual information. 
 
All safeguards for storage of information on password-protected servers with HIPAA compliant firewall will 
be in place to ensure data are secure. There is a risk that if the tablets and/or PC is lost, it will 
compromise study information. To prevent this, the tablets and/or PC devices used in this research will 
have security features that are designed to protect the device and data while enforcing strict network and 
platform security including strong passwords, remote and local wipe, network security, and certificate 
based authentication. The extensive precautions available to tablets and/or PC will minimize the risk 
involved with maintaining research databases on portable devices. 
 
Emotional Discomfort: There is a small chance that participants may become upset during assessments 
that include their history of substance use problems, psychosocial, and other potentially sensitive topics. 
These risks are not beyond usual clinical procedures in OUD treatment. We will discontinue 
administration of research instruments if a participant shows great discomfort or asks to terminate 
an interview. 
 
 
2.1.6 Protection Against Overall Risks 
 
Protections against aforementioned risks are discussed above with the description of the specific risks. 
 
This trial will be conducted in compliance with the current version of the protocol, current Good Clinical 
Practice (GCP), the principles of the Declaration of Helsinki, and all other applicable regulatory 
requirements. We will obtain written approval of the study protocol, consent form, other supporting 
documents, and any advertising for participant recruitment from the NYUMC IRB. Any amendments to the 
protocol or consent materials must be approved before they are implemented. Annual progress reports 
and local Serious Adverse Event (SAE) reports will be submitted to the IRB, according to its usual 
procedures. 
 
This study offers patients FDA-approved BUP SL treatment for opioid dependence. As such, the potential 
risks of study participation are chiefly consistent with the usual care and use of these medications in 
everyday care practice – with the aforementioned small potential increased risks of over-sedation and 
precipitated withdrawal and those of data collection (time and effort, confidentiality). As described above, 
BUP exhibits a known ceiling effect on respiratory depression, which makes it remarkably safe compared 
to other opioids, even at high doses. The pharmacologic properties of BUP, the demonstration of safety of 
the higher initial dose strategy in a case series of 94 ED patients and in other clinical trials (as described 
in Sections 2.1.1-2.1.3 our plan to administer BUP in divided doses (as opposed to a single large dose) 
and the extended duration of clinical monitoring in a clinical setting fully equipped to address all potential 
adverse events, as well as the rigorous participant selection criteria are protective factors. More 
specifically, in order to minimize physical risks, patients who consent to participation and receive 32mg 
will be monitored closely every 30 minutes for at least 90 minutes (instead of 30-60 minutes as per clinical 
practice for ED-initiated BUP) using objective and subjective assessments by trained personnel. 
Naloxone (opioid reversal agent) will be available if patients begin to exhibit any signs or symptoms of 
respiratory depression or over-sedation. Patients will be screened prior to enrollment for history of 
adverse/allergic reactions to buprenorphine or any other opioids. They will be excluded from participation 
if they have history of adverse reaction. If patients begin to experience any signs or symptoms of allergic 
reaction, the appropriate medications and equipment will be available. Patients will be discharged with 
close follow-up and assessment (as part of the study), which will minimize any physical risks of BUP 
treatment. 
 
To minimize any discomfort associated with reporting on sensitive behaviors, participants will be 
informed that they may refuse to answer questions that they are not comfortable answering. Questions 
related to eligibility determination and monitoring of safety and treatment response are not optional. If 
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decline to answer these questions, the PI will advise them that they will not be able to participate and will 
make a referral to other treatment if interested. All studies involving substance use, including this one, will 
apply for the added protection of a Federal Certificate of Confidentiality that encompasses protocol 
activity and participant data and ensure against the release of confidential information. The PI and any 
future staff will have completed requisite IRB Human Subjects and HIPAA trainings. The PI will provide 
any future staff with training in their responsibilities for maintaining participant confidentiality; we will use 
unique identifiers to identify participants in the database; all data will be kept in locked filing cabinets in 
my locked research office or on our secure server to which only the study team will have access. Study 
findings will utilize only aggregate data and no publication or presentation will involve any use of 
individual information. 
 
The study clinician will evaluate all pertinent screening and baseline assessments prior to participant 
randomization to ensure that the participant is eligible and safe to enter the study. Adverse events (AEs) 
will be assessed and documented at each visit and during phone check-ins. Individuals who experience 
an AE that compromises safe participation will be discontinued from further medication administration (as 
described in medication risks) and provided referrals for other treatment or to specialized care. 
 
 
2.1.7 Known Potential Benefits 
This study has the potential to benefit enrolled ED patients and society at large. This study will inform the 
further development of clinical protocols for the benefit of future patients with OUD; participants in this 
study will benefit from extra clinical support and expedited care coordination provided by study staff and 
may benefit from improved symptomatic treatment of OUD previously seen by higher dosing strategies. 
OUD has a large and growing public health impact, and ED patients are at particularly high risk for opioid 
associated morbidity and mortality. Treatment with BUP for OUD is associated with a variety of benefits 
including decreased fatal and nonfatal opioid overdoses, decreased opioid use, and decreased 
transmission of HIV and Hepatitis C. Yet, the vast majority of persons who would benefit from OUD 
treatment do not access this life-saving medication for reasons ranging from stigma to the need for a DEA 
X-waiver to write for a prescription of BUP and the other barriers more specific to providing BUP through 
the ED that are described in Section 2.1.3. Many ED clinicians are still early in gaining clinical experience 
with the clinical process, do not have an x-waiver to prescribe BUP, and are unaware of how to schedule 
urgent follow-up appointments. Study participants will directly benefit from having study staff available to 
provide guidance, prescribe BUP, and establish continuity of care. 
 
Further, achieving therapeutic levels earlier and maintaining them longer through the proposed rapid 
loading strategy is expected to have better treatment outcomes. Specifically, higher doses of BUP have 
been shown to provide a greater reduction in withdrawal symptoms using COWS.48 Larger initial doses of 
BUP have been associated with lower rates of treatment failure than lower initial doses.65 In a large 
meta-analysis comparing buprenorphine to methadone, medium to high doses of BUP were superior to 
low doses of BUP in effectiveness (retention in treatment and suppression of illicit opioid use).66 
 
On a societal level, defining the clinical parameters of this induction strategy may expand access to care 
for patients with OUD by addressing the aforementioned barriers that hinder programmatic 
implementation on a larger scale. Specifically, by reducing the severity of opioid withdrawal symptoms 
and craving for longer periods of time, this induction strategy would allow for more time to connect 
patients to follow-up treatment. Thereby, it would provide a practical strategy for ED providers without X- 
waivers or access to next-day follow up appointments with a BUP prescriber to initiate treatment. For 
those with OUD, widespread, simplified access to treatment is likely to reduce treatment failure, opioid 
withdrawal symptoms and craving, and morbidity and mortality associated with this condition. This study 
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3 Objectives and Purpose 
Our primary overarching aims/objective are 
1. To evaluate the feasibility, acceptability, safety and utility of a BUP 32mg SL loading dose 
induction strategy in the ED, administered as a BUP+Naloxone formulation; 
2. To determine optimal processes for an ED protocol and clinical trial. 
 
We hypothesize that enrollment of 35 ED patients with untreated OUD experiencing opioid withdrawal in 
an open-label, single arm feasibility study of a rapid BUP induction strategy using a loading dose of BUP SL 
32mg will provide the necessary information on the feasibility, acceptability, safety and utility of this 
treatment approach to identify optimal processes for the development of a treatment initiation protocol 
suitable for the ED setting so that we can properly plan subsequent large scale clinical trials. 
 
The primary endpoint is a binary global measure of successful rapid induction without clinically significant 
adverse events. This will be determined during the index visit alone, and will not be influenced by loss to 
follow up in subsequent research visits. Secondarily, we will use a wide-range of validated subjective, 
objective, and physiologic measures and patient reported outcomes at the index visit (day 0), during the 
first week (days 1, 2, and 3), and at day 30 to evaluate changes in opioid withdrawal, craving, level of 
awareness (level of activation/sedation), and other medication effects and to collect preliminary treatment 
effect and satisfaction data. 
 
3.1 Primary Objective 
1. To estimate the proportion and confidence intervals of participants who have “successful 
rapid induction” (as further defined below) amongst enrolled participants who receive a 
loading dose of BUP SL 32mg during the ED index visit. Successful rapid induction is defined 
only be the outcome of the participant’s visit, and not by any following research visits. 
 
Hypothesis: All participants who receive a loading dose of BUP SL 32mg will have successful rapid 
induction. Successful rapid induction is defined as receiving a total of 32 mg of buprenorphine SL at the 
index research visit without experiencing a clinically significant serious and/or severe adverse 
event related to the intervention. Loss to follow up in subsequent research visits will not impact this 
outcome measure. 
 
3.2 Secondary Objectives 
2. To evaluate changes in signs and symptoms of opioid withdrawal, opioid craving, level of 
awareness (activation/sedation) after administration of 32 mg BUP SL, and other medication 
effects during the index ED visit using validated subjective and objective instruments and 
physiologic measures. 
 
3. To evaluate the safety of rapid induction via adverse events checklist prior to conclusion of the 
ED index visit. 
 
4. To assess the duration of effect of BUP 32mg SL on treating opioid withdrawal and craving (days 
1-3). 
 
5. To assess patient experience domains related to treatment satisfaction and acceptability using 
self-reported measures and collecting data on reasons for non-participation in study amongst 
potentially eligible patients (at each assessment, Days 0-3 and 30). 
 
6. To collect preliminary data and explore the treatment effect on linkage to treatment, quality of life 
and additional patient-level outcomes (drug use, overdose events, healthcare use) at 30 days. 
 
Exploratory Analyses: 
To evaluate participants’ pre-study opioid use characteristics (opioid type [fentanyl or not], averaged daily 
quantity, route of administration) and other patient-level characteristics to explore their potential effect 
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4 Study Design and Endpoints 
4.1 Description of Study Design 
 
This is an open-label, single arm, single site feasibility and acceptability study in which 35 ED patient- 
participants who have untreated moderate to severe OUD and are experiencing opioid withdrawal 
(COWS score ≥ 8). will receive treatment in the ED with a loading dose of BUP 32mg SL (administered 
in divided doses) at their index visit. We will assess the feasibility, acceptability, safety, and utility of this 
intervention and provide preliminary data on the effect on opioid withdrawal, craving, and sedation as 
well as additional patient-level outcomes (engagement in treatment, drug use, quality of life, healthcare 
utilization). 
 
The first assessment will occur in-person in the ED at the index visit (day 0), and 4 additional 
appointments will be scheduled: 3 research visits and one follow-up care appointment with an OUD 
provider. Research assessments will be conducted in-person at clinical research space on 
Bellevue/NYULH campus on days 1-3, and by phone on day 30. Patients will be provided with 
appointment reminder cards with the time and location of their next appointment, and the contact 
information for the research study team. At the conclusion of their day 3 visit, participants will be given a 
prescription for BUP SL 16mg per day with a quantity sufficient to last until their scheduled clinical follow 
up appointment for ongoing treatment. The prescription will be provided earlier, at the day 1 or day 2 
research visit, if the participant reports opioid withdrawal and/or craving and has objective signs of 
withdrawal at that time. 
 
 
4.2 Data Collection and Study Measures: 
Procedures for data collection, data management, monitoring of data quality and data analysis have been 
developed and refined in our previous studies. These procedures include utilization of a computerized 
data base system (REDCap) to monitor clinical and research activities, including enrollment, adherence 
to treatment interventions, and completion of scheduled assessments. 
 
The study team will assess a range of pretreatment participant characteristics, process measures, and 
outcome using validated, reliable instruments that are widely-used, primarily derived from previous and 
ongoing studies. We will collect data and reason for non-inclusion for participants who are approached 
but not enrolled. The research team will obtain data by participant self-report, EHR abstraction, and 
contact with treatment providers. Multiple secondary endpoints using a wide-range of subjective and 
objective measures will be collected in-person at the index visit (day 0) and visits on days 1-3, and by 
phone at day 30. Details on each study visit are described in Section 7.4 (Study Schedule). 
 
 
4.2.1 Study Measures 
 
Study Measures will be selected from the Study Measures List (attached).  
5 Study Endpoints 
5.1.1 Primary Study Endpoints 
 
1. To estimate the proportion having “successful rapid induction” 
 
Successful Rapid Induction, the primary study endpoint, is defined as completing rapid induction with a 
loading dose of BUP SL 32mg without experiencing a clinically significant serious and/or severe adverse 
event (AE) related to the intervention – specifically, the receipt of a dose of BUP SL greater than 8mg 
during the Index ED visit. We will determine the proportion of participants who have successful rapid 
induction during the ED index visit amongst all study participants. 
• 
Clinically significant adverse events (AEs) include the following: over-sedation (defined as 
requiring invasive or non-invasive ventilator support, having a Richmond Agitation-Sedation Scale 
(RASS) of ≤ - 3, and/or clinician determination), hemodynamic instability (e.g., persistent 
hypotension not attributed to other causes), development of severe precipitated withdrawal 


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(clinician determination), or experiencing other unexpected, SAEs, related to receipt of the 
second dose of BUP SL (for a total of BUP SL 32mg) as defined in Section 8.1.  This measure 
will be assessed at the end of the ED index visit. 
 
• 
Precipitated withdrawal: Clinicians will assess whether an event is considered precipitated 
withdrawal. This clinical determination will be based on the severity of the withdrawal signs and 
symptoms, the rapidity of the onset of withdrawal symptoms, and clinical factors (e.g. timing since 
last use of an opioid agonist(s), type(s) of opioid agonist, duration of action of opioid agonist(s) 
used, and route of administration). Scores will be based on objective components, eliminating 
nausea which can be a side effect of BUP administration. Patients who experience precipitated 
withdrawal will be treated with ancillary medications. 
 
 
5.1.2 Secondary Study Endpoints 
 
1. To evaluate opioid withdrawal, opioid craving, sedation during of index ED visit: 
 
We will estimate the change in signs and symptoms of opioid withdrawal, opioid craving, level of 
awareness (activation/sedation) and other medication effects at repeated points of assessment during the 
index ED visit (spanning from enrollment in the study to a minimum of 90 minutes after the second 
dosage of BUP) using validated subjective and objective instruments and physiologic measures. For 
each domain (withdrawal, craving, sedation), we will determine the proportion of participants who 
experience changes in the specified measures and assess the magnitude of change and the time to 
change comparing repeated measures assessed during the index visit before treatment, after the first 
dose of BUP, and after the second dose of BUP. 
 
The primary measures for opioid withdrawal and craving will be the Clinical Opiate Withdrawal Scale 
(COWS) and Opiate Craving Scale (OCS), respectively. Complete or near complete relief of withdrawal 
and craving will be assessed primarily by the point at which patient reports this endpoint (“Tell me when 
your withdrawal/craving has gone away completely”); we will secondarily note when patient has COWS 
score, Likert, or VAS score indicating absence of withdrawal or craving. Near complete relief will be 
assessed secondarily as “gone away almost completely” and using a COWS score of <3. Oversedation 
will be defined clinically as the need for non-invasive or invasive ventilation to maintain adequate 
oxygenation and ventilation; the Richmond Agitation Sedation Scale (RASS) will be used secondarily to 
assess level of awareness (the spectrum of sedation to agitation). Relief of (or recovery from) sedation is 
when invasive or non-invasive ventilator support is no longer required, with a RASS > - 2, and when 
patient is alert enough for discharge as determined by the treating clinician. Specific measures and times 
of assessment are further described in and Section 4.2.1 (Study Measures) and Section 7 (Study 
Procedures). 
 
 
2. To evaluate the safety of rapid induction: 
 
Adverse events will be assessed using an adverse events checklist to be completed at the conclusion of 
the index visit and at each study visit. Physiologic measure (vital signs) and objective measures of level of 
awareness (agitation-sedation) will be repeatedly assessed during the index visit (as discussed in 
Secondary Endpoint 1). 
 
 
3. To assess the duration of effect of BUP 32mg SL on treating opioid withdrawal and craving 
(days 1-3). 
 
We will generate appropriate descriptive statistics using the aforementioned validated objective, 
subjective, and physiologic measures of opioid withdrawal, craving, and drug effects on days 1-3. We will 
generate proportions for the number of participants who report withdrawal, report craving, have objective 
signs of withdrawal, return to use of other opioids, and/or require prescription for BUP on days 1-3 and 
estimate the time to occurrence and confidence intervals for these events. 


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4. To assess patient acceptability 
 
Process data, including reasons for non-participation in some or all aspects of the study/clinical 
procedures, as well as self-reported measures of treatment satisfaction, good/bad treatment effects, and 
other patient experience domains (collected at each study visit/encounter) will inform acceptability. 
 
 
5. To explore treatment effect 
 
To provide preliminary treatment effect data, we will assess outcomes using measures employed in our 
other studies, such as linkage to treatment, quality of life, and additional patient-level outcomes (drug use, 
overdose events, healthcare use) at 30 days. 
 
Preliminary data of treatment effect using outcomes measures employed in our other studies will be 
collected and assessed. We will explore the effect on initial linkage to and engagement in addiction 
treatment, quality of life and functional outcomes, and additional patient-level outcomes (drug use, 
overdose events, healthcare use), including but not limited to the following: 
a. the proportion and confidence intervals of participants of patients engaged in treatment at 30 days, 
with time to initial linkage to treatment assessed secondarily; 
b. changes in self-reported non-medical opioid use over first 30 days using the timeline follow back 
method; 
c. changes in patient reported outcomes (using scales such as PROMIS GLOBAL-10 and Treatment 
Effectiveness Assessment (TEA)), self-reported healthcare utilization (non-study health services 
form) and overdose events. 
 
 
These measures will be participant self-report of engagement in treatment, confirmed by the treatment 
provider, or by direct contact with the facility and/or treating clinician and/or through EMR abstraction. 
Linkage to addiction treatment will be defined as receipt of an encounter for formal addiction treatment 
after the index ED visit. Engagement in addiction treatment will be defined as enrollment and receiving 
formal addiction treatment on the 30th day after the index ED visit. Formal addiction treatment will be 
those treatments consistent with the American Society of Addiction Medicine’s (ASAM) level of care (1-4) 
and will include a range of clinical settings, including office-based providers of BUP or naltrexone, OTPs, 
intensive outpatient, inpatient, or residential treatments. 
 
 
5.1.3 Additional Exploratory Endpoints 
 
We will explore the potential effect of patient-level characteristics on outcomes, including age, sex, 
fentanyl use, quantity of opioid use (high/low), injection/non-injection. We will explore associations 
between initial responses (change in withdrawal during the index visit) to duration of BUP treatment effect 
(as measured on Days 1-3). 
 
 
6 Study Enrollment and Withdrawal 
 
Eligible participants will be recruited from the Emergency Department at Bellevue Hospital and NYU 
Langone Health sites, including NYULH-Tisch, NYULH-Brooklyn, NYULH-Cobble Hill. The Bellevue 
Hospital ED has an annual patient volume of approximately 120,000 visits, which includes a large volume 
of patients with moderate or severe OUD who will be eligible for study participation. All patients who come 
to the Bellevue Hospital ED in opioid withdrawal may be screened by eligibility criteria for potential study 
enrollment (see Inclusion and Exclusion criteria, defined below). Patients may be referred to the study team 
by ED clinicians at NYULH sites listed above. Eligibility requirements will be determined by trained research 
staff in the ED and will be confirmed by the PI or co-investigator if there is any question of potential eligibility. 
 
6.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 


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1. Is 18 years or older 
2. Is able to speak English sufficiently to understand the study procedures and provide written 
informed consent to participate in the study. The study instruments have not been validated in 
Spanish (or other languages). Given the small size of this pilot, it would not be feasible to translate 
and validate them. 
3. Meets DSM-5 criteria for moderate to severe OUD 
4. Has used opioids within 7 days, confirmed by a positive toxicology test and/or by the 
clinical assessment by the study clinician or ED provider (e.g., self-report plus 
documented history of opioid use and objective findings consistent with opioid 
withdrawal).  
5. Denies use of methadone at a dose that is greater than 30mg within 72 hours or greater 
than 10mg within 24 hours or at an unknown dose  
6. Must be experiencing opioid withdrawal with a COWS score ≥8. 
a. Enrollment and assessments (but not study medication administration) may begin at 
COWS <8 if patient is anticipated to have a COWS score ≥ 8 during their ED visit. 
7. Is willing and able to participate in the study and follow study procedures, including completing 
a 90-minute minimum observation period in the ED after their second dose of BUP, in-person 
assessments on days 1-3, and a phone assessment on day 30. 
8. Is able to provide adequate and reliable locator information for follow-up 
9. Has reliable access to a phone 
 
6.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Is currently engaged in medication treatment for OUD with methadone, BUP, or naltrexone  
2. Currently requires prescribed opioids for treatment of an ongoing pain condition 
3. Has a known allergy to BUP 
4. Is pregnant as determined by hCG testing at the index ED visit 
5. Is breastfeeding as determined by self-report 
6. Has medical, psychiatric, or concurrent substance use conditions or severe cognitive 
impairment that might preclude safe participation in the study as determined by the study 
clinician or the clinical provider, or such that they are unable understand the study 
procedures and provide written informed consent to participate in the study 
7. Is a prisoner or in police custody at the time of the index ED visit 
8. Has previously enrolled in the current study 
 
6.3 Vulnerable Participants and Individuals 
Eligibility requirements will be determined by trained research staff in the ED, and will be confirmed by the 
PI or co-investigator if there is any question of potential eligibility. This study will not include children, 
pregnant women, prisoners, or individuals with impaired decision-making capacity. By nature of the 
population served by the Bellevue Hospital ED and NYULH EDs, participants may include economically or 
educationally disadvantaged persons, but every effort will be made to consent these patients appropriately. 
Patients may also fear that they will not receive adequate treatment for OUD, overdose or withdrawal if they 
do not consent to participate in this study. It will be made explicit that their choice to participate or not will not 
affect their treatment. If there is any question that the nature of a subject's vulnerability has influence over 
participation in the study, the subject in question will be excluded. 
 
 
6.4 Strategies for Recruitment and Retention 
As described previously, potential participants will be identified and screened after presenting to the 
Bellevue Hospital ED in opioid withdrawal. Using methods employed successfully in our previous and 
ongoing studies, potential participants will be identified by clinician referral or clinical screening. Patients 
may be referred to the study team by ED clinicians at NYULH-Tisch, NYULH-Brooklyn, NYULH-Winthrop, 
and NYULH-Cobble Hill.  
The research team will be notified of potential participants and determine whether they meet eligibility 
criteria. Subjects will be approached by trained research staff who will request the patient's verbal consent 
to inform them about the study and determine whether they are interested using an IRB-approved verbal 
consent script. Written informed consent will be obtained before any study activities are performed. After 
they are consented, we will perform additional assessments to confirm eligibility followed by pre-treatment 


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assessments as detailed in Section 6.9.4: Dosing and Administration. Individuals who meet any exclusion 
criteria will not be enrolled or will be withdrawn from the study if already enrolled as post-enrollment screen 
fails. 
 
Efforts will be made to maintain contact with patient-participants throughout the duration of the study and 
to minimize missing data. Broadly, retention methods may include outreach to the participant and their 
identified contacts through email reminders, phone calls, text messaging, and social media. 
 
A total of 35 participants will be enrolled in the study with the goal of having 30 participants complete the 
study in its entirety. 
 
 
6.4.1 Use of DataCore/Epic Information for Recruitment Purposes 
 
Patients will be recruited in-person by the research team during their ED visit without the use mail, email, 
or other messaging to patients or the use of patient-facing recruitment materials. Identification of potential 
participants will occur primarily through referral by clinical staff (health coaches, social workers, peer 
counselors, and volunteers) who operate an existing substance use screening and intervention program 
in the Bellevue ED. EPIC will be utilized in a limited capacity to identify participants. Specifically, the 
research team will review the census of current, active ED patients in EPIC to identify patients who have 
ED visits related to opioid use and/or who have been identified to have non-medical opioid use (e.g., 
nurse screening) and/or who have been identified and referred by clinical staff as potential study 
participants. The research team will inform the treating provider that their patient is potentially eligible for 
the study and will request permission to be introduced to the patient. The research team will use 
approved recruitment language to communicate the reason they are approaching the patient and ask if 
they are interested in participating in this specific study. Should the potential participants agree, the 
research team will provide the subjects with information regarding the next steps for participation. 
 
If a subject requests information regarding opting out of further recruitment for all research, subjects will 
be directed to contact research-contact-optout@nyumc.org or 1-855-777-7858. 
 
6.5 Duration of Study Participation 
The study duration will be approximately 12 months. The duration of study participation for each individual 
participant will be 1 month, including screening/index visit, study intervention and follow-up. We will target 
1 study enrollee per week, with a goal of 2 per week, and expect to enroll participants within an 11-month 
period. The study will end approximately one month after the final participant is enrolled, at the conclusion 
of that participant's one-month follow up. We know from our previous and ongoing studies that recruitment 
should not be limited by the number of eligible patients. 
 
 
6.6 Total Number of Participants and Sites 
Recruitment will end when approximately 35 participants are enrolled. Enrollment will take place out of the 
Emergency Departments in Bellevue Hospital, NYULH-Tisch, NYULH-Winthrop, NYULH-Brooklyn, and 
NYULH-Cobble Hill.  
 
6.7 Participant Withdrawal or Termination 
 
6.7.1 Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may terminate participation in the study if: 
• 
After the first 8 mg dose of BUP is administered, a study participant experiences any clinical AE 
(e.g., allergic reaction) that would preclude safe administration of the subsequent BUP 24mg 
dose during the index visit. The initial BUP 8mg is a standard dose used in the ED; it is only the 
subsequent BUP 24mg (for a total dose of BUP 32mg) that is being evaluated in this study. 
• 
Thus, if a participant develops a reaction to the initial 8mg dose, the reaction would be attributed 
to the standard dose of BUP and not the larger dose of being tested. 
• 
The participant meets an exclusion criterion (either newly developed or not previously 


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recognized) that precludes further study participation. 
• 
The participant becomes a prisoner. 
 
6.7.2 Handling of Participant Withdrawals or Termination 
If participants are terminated from the study or withdraw themselves for any of the above reasons, the 
situation will be handled accordingly. If participants choose to withdraw themselves, but have no AEs, 
they will still be eligible to continue treatment for OUD, which may include BUP, and will be treated with 
the standard of care and connected to follow-up as clinic availability allows. If participants are terminated 
or removed due to any AE, they will be monitored and treated either in the ED or on an outpatient basis. 
If a participant meets exclusion criteria (either newly developed or not previously recognized), they will 
be formally withdrawn from the study, but may be still be eligible to continue BUP treatment outside of 
the study. If participants are withdrawn or discontinued early, enrollment will continue to meet a goal of 
35 participants. 
 
6.8 Premature Termination or Suspension of Study 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to the investigator, funding agencies, and regulatory authorities. If 
the study is prematurely terminated or suspended, the PI will promptly inform the IRB and will provide the 
reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy the sponsor, IRB and/or FDA. 
 
6.9 Acquisition 
During the index visit, BUP (as a BUP-NX formulation) will be acquired from the Bellevue Hospital ED 
and NYULH Pharmacy medication dispensing system, where it is on formulary and approved for this 
indication. Upon completion of the third research visit or upon development of objective signs of opioid 
withdrawal (determined via COWS), participants will be provided with a prescription for sublingual BUP-
NX, which they can acquire free of charge from the outpatient hospital pharmacy, located adjacent to the 
BHC ED. 
 
 
6.9.1 Formulation, Appearance, Packaging, and Labeling 
 
All BUP ordered as part of clinical care in the EMR and supplied through the Bellevue Hospital Clinical 
Pharmacy and NYULH Clinical Pharmacy. Currently on Bellevue Hospital formulary is the generic 
buprenorphine/naloxone (8mg/2mg) tablet and Subutex brand BUP monoproduct (the latter would be 
for use in patients/participants with a naloxone allergy only). The manufacturer will depend on what is 
currently on the hospital formulary and may change. Should this occur, participants will receive the 
equivalent medication dose. For example, if the formulary changes from BUP-NX (8mg/2mg) tablet to 
buprenorphine/naloxone (8mg/2mg) film, the participant will receive buprenorphine/naloxone 
(8mg/2mg) film sublingually (same bioavailability/dose). 
 
Participants will also receive a prescription for BUP to pick up at their preferred outpatient pharmacy 
either after the third research visit, or when they demonstrate objective signs of withdrawal. 
 
There will be no storage or administration of medication by the research pharmacy. 
 
 
6.9.2 Product Storage and Stability 


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As above, medication will be ordered as part of clinical care and supplied through the Bellevue Hospital 
clinical pharmacy and NYULH clinical pharmacy. There will be no research medication stored/supplied by 
the study. 
 
 
6.9.3 Preparation 
The study agent does not require additional preparation. 
 
6.9.4 Dosing and Administration 
All participants will receive a total dose of BUP 32mg sublingually in divided doses during the index ED 
visit.  After the participant has received a total of 8mg (as a single dose or in divided doses), BUP SL 
24mg will be administered (i.e., 8mg + 24mg, or 4mg + 4mg +24mg).  A dose of up to BUP 8mg SL may 
be administered by the clinical provider prior to enrollment of the patient-participant (i.e., given clinically, 
not as a research procedure). 
 
After pre-medication assessments are complete and the participant is confirmed to have a COWS of ≥8, 
the participant will be given BUP SL to reach a dose of 8mg.  Starting 30 minutes after BUP 
administration, the participant will be reassessed for withdrawal severity and any adverse events. As long 
as there are no unexpected significant adverse events, an additional BUP 24mg SL will be administered. 
Then, participants will be monitored and reassessed every 30 minutes for a period of at least 90 minutes 
after receiving the last dose of BUP. 
 
Participants will return on days 1, 2, and 3 for research visits. At those visits, participants will be 
assessed for opioid withdrawal using the COWS scale. On the first day that the participant has objective 
signs of opioid withdrawal (via COWS), the Dr. McCormack, who is a licensed physician with an X-
waiver for BUP prescription, or another study clinician (with the appropriate license and X-waiver) will 
electronically send a prescription the participant’s preferred outpatient pharmacy for a daily dose of BUP 
16mg (BUP or BUP/NX 8/2mg: two SL) to start immediately. Participants will be prescribed a quantity 
sufficient to ensure medication coverage until the date of their appointment for ongoing treatment with a 
(non-study) OUD treatment provider. Participants who do not exhibit opioid withdrawal at any of the 
visits on days 1-3, will be given a prescription upon completion of the day 3 visit with instructions to self-
administer upon emergence of symptoms of opioid withdrawal or craving. 
 
All participants will receive a referral to be seen by a provider experienced in treating OUD. Thereafter, 
continued treatment and specific daily dosage of BUP-NX will be a joint decision between the study 
participant and the healthcare provider. 
 
6.9.5 Route of Administration 
BUP will be administered sublingually. 
 
6.9.6 Starting Dose and Dose Escalation Schedule 
The starting dose and dose escalation schedule will be uniform among study participants during the index 
visit of the study. The regimen will vary only on timing of dosage administration, which will be determined 
based on each individual participant’s withdrawal symptoms using various scales. After the Day 3 visit or 
if a participant has objective signs of withdrawal, a prescription for 16 mg BUP may be given to last until 
the participant’s follow-up care appointment. Continued treatment and appropriate dosage of BUP-NX for 
each participant will be determined by the OUD-experienced provider they are referred to, and will be a 
joint decision between the study participant and provider. 
 
6.9.7 Dose Adjustments/Modifications/Delays 
All study participants will receive the 32 mg loading dose of BUP at the index visit. Thereafter, dose 
adjustments can be made on an individual basis, i.e. maintenance dosing of BUP can be escalated if 
withdrawal and craving are prevalent, or can be reduced if over sedation is a concern. Study 
assessments (see Section 7.1) will help the provider determine the course of action. 
 
6.9.8 Duration of Therapy 
This study aims to pilot a novel induction strategy for long term treatment of OUD with BUP. As part of the 


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study, participants will be monitored for one month after induction, but the goal is to facilitate continuation 
of treatment beyond this study; referral to continued treatment will be provided if desired. 
 
6.9.9 Tracking of Dose 
On days 1 – 3, following the index visit, participants will participate in in-person research visits and 
complete various assessments which will include objective and subjective measures of withdrawal and 
craving, and side effects. Participants will follow-up by phone at one month and again be asked to report 
adherence, as well as other substance use (Details of assessments can be found in Sections 7.1 and 
7.3). 
 
6.9.10 Study Agent Accountability Procedures 
See Section 6.9.6. The initial 32mg loading dose of BUP will be dispensed from the Bellevue Hospital ED 
medication dispensing system and administered by a member of the research team in conjunction with 
the treating clinician. Participants will be given a prescription for BUP-NX (16mg daily in 8mg 
tablets/films) to last between their third research visit and their appointment for continuing treatment. 
 
7 Study Procedures and Schedule 
7.1 Study Specific Procedures 
 
Baseline Measures 
At baseline, socio-demographic information will be collected including age, sex, race/ethnicity, and 
housing status.. A broad range of tools selected from the Study Measures will be assessed at baseline 
and repeated at subsequent visits, include measures of substance use, opioid withdrawal and craving, 
risk behaviors, and quality of life.  A urine pregnancy test will be used to confirm study eligibility among 
females of childbearing potential unless one has been performed already clinically.  A urine and/or 
saliva toxicology test (standard drug panel plus BUP and fentanyl) will be collected for research-only 
purposes. No study-related activities  will be performed prior to obtaining written informed consent.  
 
Outcome measures 
Engagement in treatment will be assessed by self-report and verified by contact with the participant’s 
provider after the 30 day follow up visit. Tools selected from the Study Measures will also be used to 
assess substance use, functional outcome, opioid withdrawal and craving, general health, quality of life, 
and treatment preference. 
 
 
7.2 Standard of Care Study Procedures 
As part of standard clinical care, patients in opioid withdrawal will have a basic history and physical 
examination completed, including many of the assessments we will complete as study measures (e.g., drug 
use screening, DSM5, COWS). The provider may choose to obtain basic bloodwork and/or urine testing as 
indicated by clinical signs and symptoms or in anticipation of treatment. This includes, but is not limited to, 
a pregnancy test.  Toxicology tests are not routinely obtained clinically in the ED primarily because the 
available tests are not capable of detecting fentanyl (or most other synthetic opioids) and because there 
are reliable, objective clinical signs and symptoms of opioid intoxication and withdrawal.  It would be 
considered unethical to require toxicology testing to demonstrate the presence of opioid use in order for a 
patient to receive life-saving treatment (i.e., BUP) when the test itself cannot detect one of the most 
prevalent opioids being used.  As such, toxicology testing in the ED is of little utility.   
 
Whether they consent to study participation or not, all patients who present in clinical opioid withdrawal can 
receive symptomatic treatment for withdrawal. If an X-waivered provider is available in the ED, the patient will 
be able to receive BUP according to that provider's usual clinical practice. Patients with OUD can also receive 
referral for outpatient treatment and follow-up, as clinic availability allows 
7.3 Laboratory Procedures/Evaluations 
 
7.3.1 Clinical Laboratory Evaluations 
See section 7.1 and 7.2 for laboratory evaluation that may be done as part of standard of clinical care or 
study procedures.   


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7.4 Study Schedule 
 
7.4.1 Screening 
 
7.4.2 Enrollment/Baseline 
Index ED Visit (Day 0, 4 – 8 hours) 
• 
Perform baseline assessments: 
o 
Obtain demographic information, medical/psychiatric history, medication history, 
substance use history. 
o 
Obtain informed consent of potential participant verified by signature on written informed 
consent for screening form. 
o 
Perform medical examinations needed to determine eligibility based on 
inclusion/exclusion criteria. 
o 
Review history and verify inclusion/exclusion criteria. 
o 
Collect urine or saliva samples for toxicology testing, collect urine for a pregnancy test (in 
females of childbearing potential, if not performed clinically). 
o 
Assess and quantitate opioid and other substance use, withdrawal, craving, 
motivation for treatment, health status questionnaire, health services 
utilization). 
• 
Participants receive total 32mg BUP in divided doses.  After the participant has received a total of 
8mg, participants will be observed for 30 minutes to ensure that there are no adverse reactions to 
BUP-NX.  If the participant has a qualifying adverse event after the first dose (e.g., allergic 
reaction or other clinically significant AEs as described in Section 5.1.1), the second dose will not 
be given and the participant will be withdrawn from the study without receiving subsequent doses.  
Otherwise, the second dose of 24 mg will be administered. 
• 
Participants will be assessed using opioid withdrawal scales (COWS, SOWS, VAS) prior to BUP 
administration and every 30 minutes afterward for at least 90 minutes after last dose. 
• 
Participants will be discharged with 4 scheduled appointments, 3 research visits (days 1, 2, 3), 
an appointment for follow up with a BUP provider for ongoing OUD treatment, and a research 
follow-up phone call on Day 30, which marks the end of the study for the participant. 
• 
In light of the health safety risks associated with the COVID-19 pandemic, interviews may be 
conducted remotely, rather than in-person, using an approved, secure audio or audio-video 
connection (e.g., telephone, Cisco Webex) from a setting offering adequate privacy. Participants 
will be advised that they may disconnect their video feed.   
 
7.4.3 Intermediate Research Visits 
 
7.4.3.1 
Research Visits (In person, Days 1-3, 30-60 minutes) 
• 
Participants will complete assessments of withdrawal, craving, and substance use in-person daily 
for 3 days. The visits will occur either at the ED or at other clinical research space on 
Bellevue/NYU campus. In light of the health safety risks associated with the COVID-19 
pandemic, interviews may be conducted remotely, rather than in-person, using an approved, 
secure audio or audio-video connection (e.g., telephone, Cisco Webex) from a setting offering 
adequate privacy. Participants will be advised that they may disconnect their video feed.   
• 
Participants will assess themselves for symptoms of opioid withdrawal using subjective scales 
• 
At the first visit (Day 1-3) in which the participant has objective signs of withdrawal, the participant will 
be provided with a prescription for BUP.  If the participant does not have objective signs of withdrawal 
by the Day 3 visit, the prescription will be written at the conclusion of that visit. The prescription will be 
electronically sent to the participant’s pharmacy for BUP or BUP/Nx 8/2mg: 2 films/tabs taken SL daily 
for each day, starting immediately, with a quantity sufficient to last until the scheduled appointment for 


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ongoing treatment) 
• 
Participants will be assessed for adverse events, which will be recorded and reported. 
 
7.4.4 Final Study Visit (Phone) 
 
Final Study Phone Check In (Day 30+/-3, 30 minutes) 
• 
A healthcare utilization review and health questionnaire will be conducted to collect information 
on the type and amount of services received by participants. 
• 
Functional outcome will be assessed using tools selected from the Study Measures. 
• 
Attendance at follow-up treatment appointment within 1 month will be assessed by participant 
self- report and verified by contact with the provider. 
• 
Participants will be assessed for adverse events, which will be recorded and reported. 
At the conclusion of the study, the specifics of continued treatment will be a joint decision between the 
participant and the provider and will be managed by providers on a case-by-case basis. These decisions 
will not be reported to the study team. The novel part about this study is the induction strategy, but patients 
will otherwise be maintained on BUP in accordance with the standard of care. If patients wish to continue 
treatment, they will be connected with follow-up. The decision to continue will be a joint decision between 
the patient and provider. 
 
Unscheduled Visit 
If a patient is experiencing objective signs of withdrawal outside the hours of one of their research visit 
appointments, they may present to the Emergency Department for treatment. They will be asked to report 
this visit to the study team. The PI may be contacted 24 hours a day, seven days a week. 
 
7.5 Concomitant Medications, Treatments, and Procedures 
Concomitant therapy/medications will be evaluated and reviewed on an individual basis by the PI. See 
inclusion/exclusion criteria in Section 6. All concomitant prescription medications taken during study 
participation will be recorded on the study record in REDCap. For this protocol, a prescription medication 
is defined as a medication that can be prescribed only by a properly authorized/licensed clinician. 
Medications to be reported in the CRF are concomitant prescription medications, over-the-counter 
medications and non-prescription medications. 
 
7.5.1 Precautionary Medications, Treatments, and Procedures 
Patients will be made aware of the risk of using other sedating substances such as alcohol or 
benzodiazepines while taking BUP, as these may increase the risk of over sedation and respiratory 
depression. They will also be made aware of the risks of using other opioids, as the concomitant use of 
BUP and full-agonist opioids will precipitate withdrawal. 
 
7.6 Prohibited Medications, Treatments, and Procedures 
Patients will be prohibited from participating in this study if they are already receiving treatment for OUD 
with methadone, naltrexone, or BUP, or are already prescribed other opioids for pain. They will be forbidden 
from initiating any of these medications during the study, except for the BUP prescribed by the researchers. 
 
7.7 Rescue Medications, Treatments, and Procedures 
 
The ED setting and clinical staff are well-equipped to manage all potential adverse events associated with 
the study. Patients/Participants may receive treatment for other medical conditions and/or ancillary 
treatment for symptoms of opioid withdrawal (e.g., nausea, muscle aches) or sedation as clinically indicated 
in accordance with standard clinical practices. All medications, treatments, and procedures will be delivered 
as part of the clinical care of the ED visit. 
 
8 Assessment of Safety 
8.1 Specification of Safety Parameters 


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8.1.1 Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
o Note that the existing clinical protocol for the initiation of treatment with BUP in the 
Bellevue ED includes instructions for patients to return to the ED in some circumstances, 
including for repeat assessment, for social work or care management or referral 
assistance, for subsequent dose and/or prescription of BUP, for early return of withdrawal 
symptoms, etc. If return to the ED is for one of these reasons, it will not be considered an 
AE. 
• 
is considered by the investigator to be of clinical significance 
 
8.1.2 Definition of Serious Adverse Events (SAE) 
A serious adverse event (SAE) is any AE that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening 
• 
Event requiring inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect 
• 
Based on the appropriate medical judgment, may jeopardize the participant's health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition. 
 
8.1.3 Definition of Unanticipated Problems (UP) 
 
Unanticipated Problems Involving Risk to Participants or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
• 
Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• 
Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• 
Suggests that the research places participants or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
8.2 Classification of an Adverse Event 
 
8.2.1 Severity of Event 
AEs are graded according to the following scale: 
 
Mild: An experience that is transient, and requires no special treatment or intervention. The experience 
does not generally interfere with usual daily activities. This includes transient laboratory test alterations. 
Moderate: An experience that is alleviated with simple therapeutic treatments. The experience impacts 
usual daily activities. Includes laboratory test alterations indicating injury, but without long-term risk. 
 
Severe: An experience that requires therapeutic intervention and/or interrupts usual daily activities. If 
hospitalization (or prolongation of hospitalization) is required for treatment it becomes an SAE. 
 
 
8.2.2 Relationship to Study Agent 
The study uses the following AE attribution scale: 


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Not related: The AE is clearly not related to the study procedures (i.e., another cause of the event is most 
plausible and/or a clinically plausible temporal sequence is inconsistent with the onset of the event). 
Possibly related: An event that follows a reasonable temporal sequence from the initiation of study 
procedures, but that could readily have been produced by a number of other factors. 
Related: The AE is clearly related to the study procedures. 
 
 
8.2.3 Expectedness 
Dr. McCormack will be responsible for determining whether an AE is expected or unexpected. An AE will 
be considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study agent. 
 
 
8.3 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate RF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. UPs will be recorded in the data collection system 
throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 
 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
participant is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled visit (30 
days), the investigator should instruct each participant to report any subsequent event(s) that the 
participant, or the participant’s personal physician, believes might reasonably be related to participation in 
this study. The investigator should notify the study sponsor of any death or adverse event occurring at 
any time after a participant has discontinued or terminated study participation that may reasonably be 
related to this study. The sponsor should also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived offspring of a participant 
that has participated in this study. 
 
8.4 Reporting Procedures – Notifying the IRB 
 
8.4.1 Adverse Event Reporting 
AEs are identified by the research coordinator or study team during study visits and phone call check-ins. 
After discharge, AEs are assessed at time of study follow-up visits. 
All AEs and SAEs are reported according to the NYUSoM IRB's reporting guidelines. 
The PI will report the following types of adverse events to the IRB and DSMB: 
a. 
Serious AND unanticipated AND possibly, probably or definitely related events; 


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b. 
Anticipated adverse events occurring with a greater frequency than expected; and 
c. 
Other unanticipated problems involving risks to participants or others. 
These adverse events or unanticipated problems involving risks to participants or others will be reported to 
the DSMB, IRB, and FDA (if required) within 72 hours of it becoming known to the investigator, using the 
appropriate forms. The PI and DSMB will conduct a review of all adverse events upon completion of every 
study participant. The PI will evaluate the frequency and severity of the adverse events and determine if 
modifications to the protocol or consent form are required. 
 
 
8.4.2 Serious Adverse Event Reporting 
See above Section 8.4.1. 
 
8.4.3 Unanticipated Problem Reporting 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. It is the site investigator’s responsibility to report UPs to their IRB and to the study sponsor. 
The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• 
UPs that are SAEs will be reported to the IRB and to the study sponsor 72 hours of the 
investigator becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the study sponsor within 72 hours of the 
investigator becoming aware of the problem. 
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and OHRP within 72 
hours of the IR’s receipt of the report of the problem from the investigator. 
 
 
8.4.4 Reporting of Pregnancy 
As detailed previously, pregnant women will not be included in this study. If any of the study participants 
become pregnant, however, it will immediately be reported to ND or IDE sponsor, study leadership, IRB, 
and regulatory agencies. Pregnant patients will be managed with the help of experts, and on an 
individualized basis. OUD treatment can be continued throughout pregnancy, but patients must be aware 
of the risks to the fetus, both of continuing treatment and abruptly discontinuing treatment. Participants 
who become pregnant during the study will be retained in the study, unless they voluntarily remove 
themselves. 
 
8.5 Reporting Procedures – Notifying the Study Sponsor 
 
The study clinician will complete a SAE Form within the following timelines: 
 
• 
All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the SAE Form and submitted to the study sponsor within 24 hours of site awareness. See 
Section 1, Key Roles for contact information. 
• 
Other SAEs regardless of relationship will be submitted to the study sponsor within 72 hours of 
site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
the study sponsor and should be provided as soon as possible. 


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As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated event or the unanticipated problem in 
the form of a written narrative. This should include a copy of the completed Unanticipated Problem form, 
and any other diagnostic information that will assist the understanding of the event. Significant new 
information on ongoing unanticipated adverse effects shall be provided promptly to the study sponsor. 
 
 
8.6 Study Halting Rules 
Administration of study agent will be halted when three grade 3 AEs determined to be “probably related” 
are reported to the sponsor. When the third grade 3 event is reported, enrollment screens will stop 
accepting new study participants. The study sponsor will inform the DSMB members within 24 hours of 
this occurrence and will provide the DSMB with AE listing reports. The DSMB will convene an ad hoc 
meeting by teleconference or in writing as soon as possible. The DSMB will provide recommendations for 
proceeding with the study to the study sponsor. 
 
8.7 Safety Oversight 
A Data and Safety Monitoring Board (DSMB) will be established for initial and ongoing protocol review, 
including data, protocol compliance, safety and efficacy data in compliance with the IRB. 
 
Dr. Daniel Lugassy, MD, and Michael P. Bogenschutz, MD will serve as the DSMB members for this 
study. Dr. Lugassy is an Emergency Department physician and a toxicologist, and Dr. Bogenschutz is a 
Psychiatrist and addiction researcher who has extensive experience in opiate research. Dr.’s Lugassy 
and Bogenschutz will ensure  protocol compliance and data safety, and neigher have ethical conflicts, 
including financial interest related to study outcome. If necessary, they will disclose any potential conflicts 
in writing. The board will meet at least annually, and as needed if a meeting is deemed necessary by the 
study team.  
 
Day-to-day oversight of the trial is provided by the Principal Investigator (PI), Dr. McCormack. Dr. 
McCormack assures that informed consent is obtained prior to performing any research procedures, that 
all participants meet eligibility criteria, and that the study is conducted according to the IRB-approved 
research plan. Dr. McCormack will review all study data and any adverse events (AEs) according to 
protocol, and report all AEs to the DSMB chair, sponsor, and IRB. 
 
During DSMB board meetings, Dr. McCormack and other research personnel will report on the trial status, 
followed by a closed session under the direction of the DSMB chairperson, during which time the 
investigators and research team may be present. This will be followed by an executive session restricted 
to DSMB members. Issues discussed may include those related to participant safety and benefit, whether 
the primary study question is being answered, conflict of interest, confidentiality, and ongoing study review 
(including AEs, SAEs, and regulatory issues). All adverse events and unanticipated problems during follow-
up will be reported to the IRB, DSMB, and NIAAA. The PI will evaluate the frequency and severity of adverse 
events and determine if modifications to the protocol and/or consent form are required. During the review 
process, the DSMB will evaluate whether the study should continue unchanged, require 
modification/amendment, continue or close to enrollment. Either the principal investigator, DSMB, or the 
NYU IRB have the authority to stop or suspend the study or require modifications. Following the DSMB 
meeting, recommendations will be made by the chairperson to Dr. McCormack and a final report (edited by 
all DSMB members) will be prepared and submitted to the NYUMC IRB. Stopping the trial due to safety 
concerns or interim analysis of the primary outcome are not anticipated; the study medication, BUP/NX, is 
FDA-approved, and no significant safety issues have arisen. DSM Plans typically include stopping rules 
that specify the outcome differences detected between groups during an interim analysis that can result in 
stopping the clinical trial. In general, stopping rules will reflect one of the following conditions: 1) there is 
clear evidence of harm or harmful side-effects of the treatment; 2) there is not likelihood of demonstrating 
treatment benefit; 3) there is overwhelming evidence of the benefit of the treatment. Again however, 
because we are simply using a higher dose of BUP/NX to initiate treatment, which is already FDA-approved 
for the indication in question, and since data from other studies do not suggest significant safety 
considerations, early stopping on the basis of clear benefit (yes/no) is not anticipated. 
 
9 Clinical Monitoring 


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Clinical site monitoring is conducted to ensure that the rights and well-being of human participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). 
 
• 
As described in Section 8.7, Dr. McCormack will oversee the study in its entirety and ensure that 
human participants safety and wellbeing is protected, that all data is carefully reviewed, and that 
all adverse events are appropriately reported. 
 
10 Statistical Considerations 
10.1 Statistical and Analytical Plans (SAP) 
 
The overall findings of the study will be used to assess the feasibility, acceptability, and utility of initiating a 
BUP loading dose in ED patients and linking patients to ongoing OUD treatment. Statistical analyses will 
consist of descriptive analyses for the primary outcome (proportion of participants successfully induced via 
loading dose), and secondary outcome measures (opioid withdrawal and craving scores, time to next BUP 
dose, opioid and other illicit drug use, proportion making a successful transition to an outpatient clinic). 
Measures of central tendancy (the mean), and the variability (standard deviation) of the study participant 
characteristics and for other participant-reported or objectively evaluated measures will also be calculated. 
Summary tabulations and measures of central tendency, variance, and other distributional properties of the 
obtained results will be presented. Where applicable, we will also conduct cross-tabulations and 
comparative analyses of variance based on selected key characteristics of the study participants (e.g., sex, 
age categories, baseline opioid requirement). This is a pilot study aimed at producing preliminary data 
which will inform future large-scale studies. Our analyses will be purely descriptive and we will not attempt 
to show an effect size, thus there is no power calculation for this sample size, it is based on feasibility. 
 
Our a priori hypotheses of the potential effect of patient characteristics on outcomes will be tested in 
subsequent large scale studies. The outcomes obtained in the proposed pilot study will also be compared 
with benchmark data based on the results of our previous studies with similar patient populations and other 
available recent or contemporaneous research and clinical data. Adverse events recorded in the study will 
be reported using both quantitative tabulations and qualitative descriptions.  
 
10.2 Measures to Minimize Bias 
 
10.2.1 Enrollment/Randomization/Masking Procedures 
This open label, single arm study does not involve any randomization or blinding. Study participants will be 
recruited by convenience, and participants will receive the 32mg BUP induction dose. Analysis of the study 
outcomes will facilitate planning of clinical protocols for treatment of OUD and future large scale studies 
using this novel induction approach. 
 
11 Source Documents and Access to Source Data/Documents 
 
All study data will be entered into REDCap, a secure, HIPAA-compliant database platform, and unique 
study ID’s will be used to de-identify participants’ data. REDCap is currently approved by NYU MCIT to 
store data containing PHI. Data will be stored on secure servers and/or in locked filing cabinets in a 
locked research office with access only to authorized study personnel as identified by the principal 
investigator and project manager for this study. Dr. McCormack will permit study-related audits and 
monitoring as required by the IRB, the sponsor, government, or any University regulatory, compliance, or 
quality assurance group who is authorized to review the study. 
 
12 Quality Assurance and Quality Control 
 
QC procedures will be implemented beginning with the data entry system and data QC checks that will be 
run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 


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Following written SOPs, the monitors will verify that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
 
The investigational site will provide direct access to all study related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
 
 
13 Ethics/Protection of Human Subjects 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
 
13.1 Ethical Standard 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must be 
obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
 
13.2 Institutional Review Board 
 
13.2.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. This protocol has been submitted with the Informed Consent 
Form, verbal consent script and study overview sheet. Informed written consent will be obtained prior 
to any study activities. 
 
13.2.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. It will take place in the Emergency 
Departments of Bellevue Hospital, NYULH-Tisch, NYULH-Brooklyn, NYULH-Winthrop, NYULH-Cobble 
Hill. Extensive discussion of risks and possible benefits of participation will be provided to the participants 
and their families. Consent forms will be IRB-approved and the participant will be asked to read and 
review the document. The investigator will explain the research study to the participant and answer any 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written consent form 
and ask questions prior to signing. The participants should have the opportunity to discuss the study with 
their surrogates or think about it prior to agreeing to participate. They will be required to sign the informed 
consent document prior to any procedures being done specifically for the study. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the signed informed consent 
document will be given to the participants for their records. The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the participant’s research record, which 
will be kept in locked filing cabinets in a locked research office with access only to authorized study 
personnel as identified by the PI and project manager. The consent process, including the name of the 
individual obtaining consent, will be thoroughly documented in the participant’s research record. Any 
alteration to the standard consent process (e.g. use of a translator, consent from a legally authorized 
representative, consent document presented orally, etc.) and the justification for such alteration will 
likewise be documented. 
 


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13.3 Informed Consent Process 
 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The Informed Consent Form has been submitted with this 
protocol. The research staff obtaining consent may be located remotely (outside of the ED) with 
communication occurring by telephone or IRB-approved virtual technologies (i.e., WebEx) and 
consent completed using a paper informed consent form or electronically captured using REDCap 
software. Electronically signed informed consent documents will be maintained within the REDCap 
data system in accordance with approved guidelines. 
 
Any patient who is unable understand the study and provide written informed consent to participate will be 
excluded, and this could include anyone who has a medical, psychiatric or cognitive impairment, as well as 
someone who is currently too intoxicated to understand and consent to participation in the study.  Dr. 
McCormack has extensive experience working with ED patients who have substance use disorders and 
enrolling them in research studies, and has developed methods of quizzing patients on the study purpose, risks, 
and benefits, to ensure their understanding of the study. We will assess all potential participants with exact or 
modified questions selected from the University of California, San Diego Brief Assessment of Capacity to 
Consent (UBACC), which can be viewed at 
https://irb.nyspi.org/themes/doc/Literature.Jeste.DecisionalCap.IRBmbr.Dec2017.pdf. Dr. McCormack has 
published on the topic of including ED patients with alcohol use disorder in research, and showed the feasibility 
of using the UBACC to assess consent (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530610/). 
  
Specific questions we will ask include: 
  
1. What is the purpose of the study that was just described to you? 
2. What makes you want to consider participating in this study? 
4. Do you have to be in this study if you do not want to participate? 
5. If you withdraw from this study, will you still be able to receive regular treatment? 
6. If you participate in this study, what are some of the things that you will be asked 
to do? How many times will you be asked to come back for research visits? 
7. Please describe some of the risks or discomforts that people may experience 
if they participate in this study. (Please describe the 2 serious risks associated 
with the study.) 
8. Please describe some of the possible benefits of this study. 
9. Is it possible that being in this study will not have any benefit to you? 
  
It is important to note that treatment with buprenorphine requires the patient to be experiencing withdrawal 
symptoms, so no patients who are currently under the influence of drugs will be eligible for the study. Rather, 
they may be re-assessed for eligibility at a later time. 
 
13.4 Participant and Data Confidentiality 
 
Information about study participants will be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a 
signed participant authorization informing the participant of the following: 
• 
What protected health information (PHI) will be collected from participants in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research participant to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of participant 
authorization. For participants that have revoked authorization to collect or use PHI. 
 


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The following procedures have been put in place to minimize this risk. Patients will be fully informed that 
information collected during the study will be kept confidential and be available only to the research team. 
The PI will apply for an NIH Certificate of Confidentiality to encompass protocol activity and participant data 
and ensure against the release of confidential information. This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to research 
records to refuse to disclose identifying information on research participation in any civil, criminal, 
administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
researchers and institutions from being compelled to disclose information that would identify research 
participants, Certificates of Confidentiality help achieve the research objectives and promote participation 
in studies by helping assure confidentiality and privacy to participants. 
 
Data will be de-identified and unique identifiers will be used. We will use data collection and handling 
measures that are secure and compliant with HIPAA, Bellevue Hospital Center, and NYULH. Screening 
data and volunteer survey data will be entered into REDCap, a secure, HIPAA-compliant database platform. 
REDCap is currently approved by NYU MCIT to store data containing PHI. Data will be stored on secure 
servers and/or in locked filing cabinets in a locked research office with access only to authorized study 
personnel as identified by the principal investigator and project manager for this study. 
 
All research assistants and others involved in the study will be required to complete appropriate IRB Human 
Subjects and HIPAA trainings. The principal investigator will be responsible for ensuring that all staff 
involved in the study understand and follow all human participants' confidentiality protection measures. Any 
potential breaches of confidentiality will be reported to the study PI, who will report such breaches to the 
IRB and any appropriate regulatory and funding agencies, and take any further corrective measures as 
appropriate. Study findings will be presented using only aggregate data; no publication or presentation will 
involve use of any individually identifying information. 
 
13.4.1 Research Use of Stored Human Samples, Specimens, or Data 
Intended Use: Data collected under this protocol may be used to study ED-based treatment of OUD 
using BUP. No genetic testing will be performed. 
 
14 Data Handling and Record Keeping 
14.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents will be completed in an organized manner to ensure accurate interpretation of data. 
Most data will be recorded electronically, but when necessary, hard copy CRFs will be completed with 
black ink to ensure clarity of reproduced copies. Any changes or corrections will be indicated with a single 
line crossing out the original entry. 
 
Electronic CRFs (eCRF) will used in REDCap, and any hard copy CRFs will be recorded in REDCap 
after the participant is enrolled. Any discrepancies between a paper and electronic CRF will be explained 
and captured in a progress note and maintained in the participant’s official electronic study record in 
REDCap. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into REDCap. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. 
 
14.2 Study Records Retention 
 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication. No records will be destroyed without the written consent of the sponsor. It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to be 
retained. 
 


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14.3 Protocol Deviations 
 
Any departure from procedures and requirements outlined in the protocol will be classified as either a major 
or minor protocol deviation. The difference between a major and minor protocol deviation has to do with the 
seriousness of the event and the corrective action required. A minor protocol deviation is considered an 
action (or inaction) that by itself is not likely to affect the scientific soundness of the investigation or seriously 
affect the safety, rights, or welfare of a study participant. Major protocol deviations are departures that may 
compromise the participant safety, participant rights, inclusion/exclusion criteria or the integrity of study 
data and could be cause for corrective actions if not rectified or prevented from re-occurrence. The principal 
investigator will be responsible for developing corrective action plans for both major and minor deviations 
as appropriate. Those corrective action plans must be approved by the IRB of record. All protocol deviations 
will be monitored for (1) significance, (2) frequency, and (3) impact on the study objectives, to ensure that 
they do not compromise the integrity of the trial. 
All protocol deviations will be recorded in the participant’s study record. Dr, McCormack must be contacted 
immediately if an unqualified or ineligible participant is enrolled into the study. 
Additionally, all research assistants and those involved in the study are responsible for reviewing the IRB 
of record’s definition of a protocol deviation or violation and understanding which events need to be 
reported. Researchers must recognize that the IRB definition of a reportable event may differ and act 
accordingly in following all reporting requirements for both entities. 
 
14.4 Publication and Data Sharing Policy 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures obtained in 
patients or participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and 
the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National 
Library of Medicine. Other biomedical journals are considering adopting similar policies. For interventional 
clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s responsibility 
to register the trial in an acceptable registry, so the research results may be considered for publication in 
ICMJE member journals. The ICMJE does not review specific studies to determine whether registration is 
necessary; instead, the committee recommends that researchers who have questions about the need to 
register err on the side of registration or consult the editorial office of the journal in which they wish to 
publish. 
 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register 
and report results of certain "applicable clinical trials": 
 
• 
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations 
of a product subject to FDA regulation; 
• 
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric post-market surveillance studies. 
• 
NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 
 
15 Study Finances 
15.1 Funding Source 


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The study will be funded by the Emergency Medicine Foundation (EMF) and the NYU Clinical and 
Translational Science Institute (CTSI). 
 
 
15.2 Costs to the Participant 
Participants are not expected to face any additional costs by participating in this study. Participants will be 
ED patients recruited during their ED visit. They will be billed for the costs of medical care during that 
encounter, if the expenses would have happened even if they did not choose to participate in the study. If 
they have health insurance, the cost of these services will be billed to their insurance company. If their 
insurance does not cover these costs or they do not have insurance, the costs will be their responsibility. 
The study medication (BUP) will be provided as part of clinical care and including in the billing of their 
clinical services. All participants will be patients who are eligible and interested in receiving treatment 
for OUD with BUP. As such, the study medication is the same medication that they would have otherwise 
received during routine care of their ED visit but at a higher dose. They will not have to pay for the 
research urine or saliva drug screen(s), but will be responsible for any other laboratory studies that are 
part of routine care. Participants will be compensated for their time to complete research assessments 
and transportation for follow-up (see Section 15.3). Receiving BUP at the dose indicated by this study 
protocol (32 mg) will not impact insurance coverage for patients. 
 
 
15.3 Participant Reimbursements or Payments 
Payment will be provided reimbursement for participation in this study. Payment will be distributed 
incrementally for each follow-up treatment visit or off-site survey in which the participant participates. This 
population consists of a large volume of patients with OUD or other substance use disorders who do not 
regularly receive healthcare; without some payment and financial aid in commuting back and forth to visits, 
it is much more unlikely that patients will follow-up and complete the study. The total amount of 
compensation was carefully considered to come up with an amount that provides enough incentive for 
participation, but is unlikely to deceive people into participating. 
 
$80 value will be provided at initial recruitment in the Emergency Department for study participation. 
Participants will receive $40 value for each in-person research visit on days 1, 2, and 3 of the study, and 
receive a total of $120 value for completing all three. $40 will also be provided for the follow up phone call 
at Month 1. A total of $240 value will be disbursed to each participant. Participants will also be provided with 
Metrocards or car service (Uber, Lyft) within the NYC Metropolitan area. 
 
For methods of compensation, participants can choose either the full value on a Clincard or a smartphone 
with a 30-day service plan plus the additional value on a Clincard. We anticipate the cost of the phone will 
be approximately $5-$20, and the cost of 30-days of cellular service is $20. For example, if a participant 
chooses to receive a phone and 30-day service plan during the index visit, they will also receive $40-$55 
on the ClinCard.  
 
16 Study Administration 
16.1 Study Leadership 
 
The study will be led and supervised by Dr. Ryan McCormack. 
 
17 Conflict of Interest 
 
The investigators report no conflicts of interest. 
 
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