Clinical trial NCT05425420
Conditions: Pain, Postoperative
Sponsor: Kanecia Obie Zimmerman
Start date: 2023-08-11; Completion date: 2024-01-20
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Single-center, open label, single-session study to evaluate methadone pharmacokinetics and pharmacodynamic in adults.

Detailed description:
The Adult Methadone study will be conducted at a single site, Duke Early Phase Research Unity (DEPRU), to enroll 24 participants. Participants will be treated/monitored overnight with Methadone hydrochloride IV (FDA approved and commercially available), with daily follow-up visits for 1 week total. The study aims to provide information on the disposition and clinical effects of intravenous methadone to update the drug label.

Arms: arm 1: All participants will be treated with Methadone Hydrochloride IV (over 10 minutes) and monitored overnight.
Interventions: intervention 1: methadone hydrochloride 0.1mg/kg
Intervention descriptions: intervention 1: Single dose of methadone hydrochloride administered via intravenous (IV)

Protocol documents:
Prot_SAP_001.pdf: 
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Pediatric Trials Network: 
Best Pharmaceuticals for Children Act 
 
 
Pharmacokinetics, pharmacodynamics, and safety of a single 
dose intravenous methadone in healthy adult volunteers 
(MTH02) 
 
Phase: 1/2 
 
Funding Sponsor: 
The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD) 
 
Funding Mechanism:  PTN 2.0 TO5 
 
Protocol Date: 
27NOV2023 
Protocol Version: 
6.0 
IND Number: 
119459 
NCT Number: 
NCT05425420 
IND Sponsor/PTN Principal 
Investigator:   
 
Kanecia Zimmerman, MD, PhD, MPH 
Associate Professor of Pediatrics  
Duke Clinical Research Institute 
300 West Morgan Street, Durham, NC 
27710 
Phone: 919-668-8651 
Fax: 919-681-9457 
E-mail: kanecia.zimmerman@duke.edu 


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STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Council for 
Harmonisation (ICH) E6(R2) guideline for Good Clinical Practice (GCP), and the applicable 
regulatory requirements from the United States (U.S.) Code of Federal Regulations (CFR), 
including 45 CFR 46 (Human Subjects Protection); 21 CFR 312 (Investigational New Drug); 21 
CFR 50 (Informed Consent), 21 CFR Part 54 (Financial Disclosure), and 21 CFR 56 
(Institutional Review Board [IRB]); as well as international regulatory requirements, if applicable. 
All individuals who are responsible for the conduct, management, or oversight of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
 
 
 
 


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SITE PRINCIPAL INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and the investigator brochure or package 
insert/product label, and I agree that the protocol and associated documents contain all 
necessary details for my staff and me to conduct this study as described. I will personally 
oversee the conduct of this study as outlined herein and will make a reasonable effort to 
complete the study within the time designated. I agree to make all reasonable efforts to adhere 
to the attached protocol. 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by the sponsor or the sponsor’s representative. I will discuss this 
material with study personnel to ensure that they are fully informed about the efficacy and safety 
parameters and the conduct of the study in general. I am aware that, before beginning this 
study, the Institutional Review Board (IRB) responsible for such matters must approve this 
protocol in the clinical facility where it will be conducted. 
I agree to either obtain legally effective informed consent from participants as required by the 
IRB of record and according to government regulations and ICH guidelines. I further agree to 
report to the sponsor or its representative any adverse events in accordance with the terms of 
this protocol and the U.S. CFRs, Title 21, part 312.64, ICH GCP 4.11, as well as international 
regulatory requirements, if applicable. I further agree to ensure the study is conducted in 
accordance with the provisions as stated and will comply with the prevailing local laws and 
customs. 
 
 
 
 
 
 
Site Principal Investigator Name (Print) 
 
 
 
 
 
 
Site Principal Investigator Signature 
 
Date 
 
 
 


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PTN PRINCIPAL INVESTIGATOR AND IND SPONSOR SIGNATURES 
The signature below documents the review and approval of this protocol and associated study 
materials (e.g., Manual of Procedures, package inserts), and provides the necessary 
assurances that this clinical study will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality and according to local legal and regulatory 
requirements and to the principles outlined in applicable U.S. and international regulations and 
ICH guidelines. 
 
 
Kanecia Zimmerman, MD, PhD, MPH 
PTN Principal Investigator/IND Sponsor Name 
(Print or Type) 
PTN PI/IND Sponsor Signature 
Date 
IND Sponsor (if different from above) 
IND Sponsor’s Signature 
Date 
 
 
 
 


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TABLE OF CONTENTS
STATEMENT OF COMPLIANCE .................................................................................................. ii
SITE PRINCIPAL INVESTIGATOR STATEMENT....................................................................... iii
PTN PRINCIPAL INVESTIGATOR AND IND SPONSOR SIGNATURES .................................. iv
TABLE OF CONTENTS................................................................................................................. v
LIST OF TABLES.......................................................................................................................... ix
LIST OF ABBREVIATIONS ........................................................................................................... x
PROTOCOL HISTORY OF CHANGES....................................................................................... xii
PROTOCOL SYNOPSIS........................................................................................................... xviii
SCHEMATIC OF STUDY DESIGN ............................................................................................. xix
1
KEY ROLES ........................................................................................................................ 20
2
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................................... 21
Background Information........................................................................................... 21
Background of Methadone Hydrochloride................................................... 21
Adult Labeling of Methadone Hydrochloride ............................................... 24
Scientific Rationale .................................................................................................. 24
Potential Benefits..................................................................................................... 24
Known Potential Risks............................................................................................. 24
Risks of Blood Drawing................................................................................ 25
Risk of Drug and Food Interactions............................................................. 26
Risk of Intravenous (IV) Infusion and Taking Blood from IV....................... 26
Potential Risk of Loss of Confidentiality ...................................................... 26
Pregnancy Risks.......................................................................................... 26
Unforeseen Risks......................................................................................... 26
3
OBJECTIVES AND OUTCOME MEASURES.................................................................... 27
4
STUDY DESIGN.................................................................................................................. 28
Study Design............................................................................................................ 28
Study Product or Intervention.................................................................................. 28
Rationale for Dose Selection....................................................................... 28
Duration of Participant Participation........................................................................ 28
Biological Specimen Collection ............................................................................... 28
DOI-specific Testing................................................................................................. 29
Events of Special Interest........................................................................................ 29
Safety ESIs .................................................................................................. 29
Efficacy ESIs................................................................................................ 29
Study Definition of Enrollment ................................................................................. 29
Study Definition of Enrollment into Active Study......................................... 29
Screen Failures........................................................................................................ 29


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Study Definition of Completion ................................................................................ 29
Participant Completion* ............................................................................... 29
Study Completion......................................................................................... 29
5
STUDY POPULATION........................................................................................................ 30
Selection of the Study Population/Sample Size...................................................... 30
Inclusion/Exclusion Criteria...................................................................................... 30
Participant Discontinuation/Withdrawal................................................................... 31
Participant Decides to Withdraw Consent................................................... 31
Participant Decides to Withdraw from Study Intervention........................... 31
Study Investigator/Sponsor Decides to Withdraw Participant..................... 31
Replacements.............................................................................................. 31
6
STUDY PROCEDURES ...................................................................................................... 32
Summary of Procedures.......................................................................................... 32
Screening/Enrollment (Day -30 to 0)....................................................................... 33
Inpatient Visit (Day 0, Hour 0 - 30) .......................................................................... 34
Follow-Up (48 to 72 hours post-drug administration).............................................. 35
Final Study Visit (96 hours post-drug administration) ............................................. 35
Early Study Withdrawal Visit.................................................................................... 35
Specimen Collection for Study-Specific Tests ........................................................ 36
Urine Collection............................................................................................ 36
Screening laboratory assessments ............................................................. 36
Pharmacokinetic Tests ................................................................................ 36
PK Sampling Schedule................................................................................ 36
Maximum Blood Volumes............................................................................ 37
Study-specific Procedures....................................................................................... 37
Electrocardiogram........................................................................................ 37
Pupillometry, Dark-Adapted......................................................................... 37
Vital Signs .................................................................................................... 37
Observed Sedation, MOAA/S...................................................................... 37
Thermal Pain Tolerance Threshold............................................................. 38
Subjective Self-assessment ........................................................................ 38
Summary of Study-specific Procedures ...................................................... 39
Study-specific PK Specimen Preparation, Handling, Storage, and Shipping......... 40
7
STUDY PRODUCT DESCRIPTION.................................................................................... 41
Study Product Information ....................................................................................... 41
Dosage and Dose Timing ............................................................................ 41
Formulation, Packaging, and Labeling........................................................ 41
Product Storage and Stability...................................................................... 41
Preparation and Administration ................................................................... 41
Accountability Procedures for the Study Product.................................................... 41
Replacement Doses..................................................................................... 42
Disposition of Study Products Upon Study Completion or Expiration ........ 42
Concomitant Medications/Treatment Restrictions .................................................. 42


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ASSESSMENT OF SAFETY............................................................................................... 43
Specification of Safety Parameters ......................................................................... 43
Guidelines for Assessing Association of an Adverse Event ................................... 43
Guidelines for Assessing Intensity of an Adverse Event ........................................ 44
Guidelines for Assessing Causality......................................................................... 44
Safety Events of Special Interest  ............................................................... 44
Collection Period and Reporting Procedures.......................................................... 44
Safety Event Follow-up and Sponsor Reporting ..................................................... 45
Discontinuation of a Participant Due to Adverse Events ............................ 45
Pregnancy................................................................................................................ 46
Regulatory Reporting............................................................................................... 46
Data and Safety Oversight (Medical Monitor/Data Safety Monitoring Board)........ 46
9
STUDY TERMINATION / HALTING ................................................................................... 48
Study or Site Halting Criteria / Termination Criteria................................................ 48
Halting Rules............................................................................................................ 48
10
CLINICAL MONITORING.................................................................................................... 49
11
STATISTICAL CONSIDERATIONS ................................................................................... 50
Study Endpoints....................................................................................................... 50
Primary Endpoints........................................................................................ 50
Secondary Endpoints................................................................................... 50
Exploratory Endpoints.................................................................................. 50
Analysis Population.................................................................................................. 50
Analysis Plan............................................................................................................ 51
Primary Analysis .......................................................................................... 51
Secondary Analysis ..................................................................................... 52
Exploratory Analysis .................................................................................... 52
Demographics and Baseline Characteristics .......................................................... 53
Planned Interim Analyses........................................................................................ 53
Sample Size Considerations ................................................................................... 53
12
FUTURE USE OF STUDY RECORDS AND BIOLOGICAL SPECIMENS........................ 54
13
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................. 55
14
QUALITY CONTROL AND QUALITY ASSURANCE........................................................ 56
15
ETHICS/PROTECTION OF HUMAN PARTICIPANTS ...................................................... 57
Informed Consent Process ...................................................................................... 57
Informed Consent of Adult Participants....................................................... 57
Documentation of Permission, Assent, and Consent.............................................. 57
Confidentiality and Privacy ...................................................................................... 58
16
DATA HANDLING AND RECORD KEEPING.................................................................... 59
Data Handling .......................................................................................................... 59
Data Management Responsibilities......................................................................... 59
Data Capture Methods............................................................................................. 59


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Types of Data........................................................................................................... 59
Timing/Reports......................................................................................................... 59
Study Records Retention......................................................................................... 59
Protocol Deviations.................................................................................................. 60
17
PUBLICATION POLICY...................................................................................................... 61
18
LITERATURE REFERENCES ............................................................................................ 62


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LIST OF TABLES 
Table 1. Documented use of methadone in the acute setting ..................................................... 22 
Table 2. Methadone PK during treatment of acute pain .............................................................. 23 
Table 3. Schedule of study procedures and assessments .......................................................... 32 
Table 4. Optimal PK sampling schedule relative to single dose of methadone .......................... 36 
Table 5. Schedule of study-specific procedures .......................................................................... 39 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
AUC 
Area Under the Concentration Time Curve 
BP 
Blood Pressure 
BPCA 
Best Pharmaceuticals for Children Act 
BUN 
Blood Urea Nitrogen 
BMP 
Basic Metabolic Panel 
CFR 
Code of Federal Regulations 
CL 
Clearance 
Cmax 
Maximum Concentration 
Cmin 
Minimum Concentration 
CMP 
Complete Metabolic Panel 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
DCF 
Data Collection Form 
DCRI 
Duke Clinical Research Institute 
DEPRU 
Duke Early Phase Research Unit 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ESI 
Events of Special Interest 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDS 
Investigational Drug Services 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
Ke 
Elimination Rate Constant 
Kg 
Kilogram 
MedDRA  
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
MM 
Medical Monitor 
Μg 
Microgram 
MOAA/S 
Modified Observer’s Alertness Sedation Scale 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NIH 
National Institutes of Health 
NICHD 
National Institute of Child Health and Human Development 
NONMEM 
Non-linear Mixed Effects Modeling 


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PD 
Pharmacodynamics 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PKAP 
Pharmacokinetic analysis plan 
PTN 
Pediatric Trials Network 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SM 
Safety Monitor 
SOP 
Standard Operating Procedure 
SpO2 
Oxygen Saturation 
SUSAR 
Serious, Unexpected, Suspected Adverse Reaction 
TDS 
Technology and Data Solutions 
Tmax 
Time to Research Maximum Concentration 
t1/2 
Half-life 
VAS 
Visual Analog Scale 
Vz 
Volume of Distribution at the Terminal Phase 
 
 
 
 
 


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PROTOCOL HISTORY OF CHANGES 
 
Version 
Date 
Summary of Changes 
v1.03 
20JUL2022 
N/A, original protocol 
v2.0 
01DEC2022 
• Changed title from “Methadone pharmacokinetics and 
pharmacodynamics in adults” to “Pharmacokinetics, 
pharmacodynamics, and safety of a single dose intravenous 
methadone in healthy adult volunteers (MTH02)” 
• Changed principal investigator from Evan Kharasch to 
Kanecia Zimmerman 
• Made background information more concise and added 
reference tables – Table 1 and Table 2 (Section 2) 
• Changed or more clearly defined objectives (Section 3) 
o Primary objective changed from "Methadone enantiomers 
plasma concentrations vs time; primary and secondary 
pharmacokinetic parameters" to "Characterize the PK of 
methadone hydrochloride injection" 
o Secondary objective changed from "Methadone enantiomers 
hepatic clearance, hepatic extraction; EDDP enantiomers 
plasma AUC, Cmax, elimination half-life, EDDP/methadone 
AUC ratio; analgesia (maximum tolerated temperature 
threshold and AUC0-120), miosis (maximum, AUC0-120), 
minimum respiratory rate; maximum end-expired carbon 
dioxide concentration, maximum sedation" to (1) 
"Characterize the PD effect of methadone hydrochloride 
injection" and (2) "Characterize the safety profile of 
methadone hydrochloride injection" 
o Exploratory objective changed from "Methadone enantiomers 
renal clearance, EDDP enantiomers formation clearance; 
miosis, analgesia and respiratory Emax, EC50, t1/2ke0, 
subjective effects magnitude, influence of CYP2B6 genotype 
on primary and secondary outcomes, influence of age on 
primary and secondary outcomes" to "Characterize 
exposure-response relationships" 
• Changed/refined outcome measures and endpoints for 
relevance and clarity to match objectives (Section 3) 
• Reduced timeline from 120 to 96 hours (Section 4) 
• Made QTc a safety event of special interest (Section 4.6.1) 
• Added efficacy events of special interest: miosis, ventilation, 
analgesia (Section 4.6.2) 
• Expanded inclusion age max from 39 to < 40 (Section 5.2) 
• Edited exclusion criteria (Section 5.2) 
o Expanded exclusion criteria, based on further research, to 
include the following: 
 History of cardiac dysfunction 
 History of or current QTc prolongation, defined as > 470 
ms in males and > 480 ms in females 


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 Known hypersensitivity to methadone hydrochloride or 
any other ingredient in the methadone hydrochloride 
injection 
 Known acute bronchial asthma or hypercarbia 
 Receipt of a serotonergic drug or bupropion within 7 days 
prior to study enrollment  
 Receipt of benzodiazepines, muscle relaxants, or other 
opioids within 7 days prior to study enrollment 
 CYP2B6 inhibitors: macrolide antibiotics, azole-antifungal 
agents, fluconazole, Alstonia boonei, Mangifera indica, 
and Picralima nitida  
 CYP2B6 inducers: abacavir, amprenavir, nevirapine, 
telaprevir 
 Receipt of zidovudine, desipramine, or other drugs that 
may increase serum concentration when combined with 
methadone 
 Known or suspected gastrointestinal obstruction, 
including paralytic ileus 
 Significant respiratory depression 
o Qualified CYPB26 exclusion to be for moderate or strong 
CYP2B inhibitors and inducers 
o Added herbal exclusions, so removed statement expressing 
none are known 
o To CYP2B6 exclusion, added "in last 30 days" 
o Removed rationale for obesity (BMI > 33) exclusion 
• Expanded language regarding participant 
discontinuation/withdrawal (Section 5.3) 
• Defined early withdrawal as a participant who has had < 5 
specimens obtained (Section 5.3.4) 
• Updated study procedures (Section 6)  
o Updated the table of procedures and assessments (Table 3)  
 More inclusive of all procedures 
 Replaced shaded boxes with Xs 
 Time is across the top columns instead of down rows 
 Separated PK sampling schedule into separate table 
(Table 4) 
 Separated PD measures, study-specific procedures, into 
separate table (Table 5) 
o Edited time series for PK sampling schedule and study-
specific procedures 
o Added COVID-19 test  
o Added urine drug screen and breathalyzer 
o Changed ECG time points to study drug administration and 
24 hours after study drug administration 
o Reduced study drug follow-up from 120 to 96 hours 
o Added an early study withdrawal visit (Section 6.6) 
o Added to clinical laboratory evaluations CMP (complete 
metabolic panel) and AAG (alpha-1-acid glycoprotein) 
(Section 6.7) 
 
 


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• Reduced the number of PK blood draws from 30 to 18 
(Section 6.7.4) 
• Reduced the volume of blood collected from 5 cc/sample to 
3.0 cc/sample (Section 6.8.3)  
• Reduced the max number of blood draws to 20 (Section 6.8.3)  
• Made study-specific procedure text more precise (Section 6.8)  
• Reduced the number of pharmacodynamic assessment time 
points and the number of study-specific procedures (Table 5) 
• Added formulation, packaging, and labeling information 
(Section 7.1.2) 
• Added replacement dose information (Section 7.2.1) 
• Changed non-study drug abstinence prior to study drug 
administration from 2 to 30 days (Section 7.3) 
• Expanded text regarding ethics (Section 15)  
• Expanded text regarding data handling (Section 16) 
• Added text for publication policy (Section 17) 
• Removed use of arterial lines 
• Removed use of safety labs 
• Removed target for 25% minority population 
• Removed statement about document translation for non-
English speakers. 
• Minor administrative changes including, but not limited to, 
formatting, punctuation, grammar, abbreviations 
v3.0 
20FEB2023 
• Changed ECG options from 3 or 5 to 5 or 12 
• Edited halting rule language (Section 9.2) 
• Changed that methadone hydrochloride will be prepared in 
IDS, not DEPRU (Section 7.2) 
• Removed 10-minute duration for methadone injection (Section 
7.1.4) 
• Changed term of ‘site PI’ and ‘study investigator’ to ‘Study PI’ 
for consistency 
• Minor administrative changes including punctuation 
v4.0 
03MAY2023 
• Eliminated Alpha-1 acid glycoprotein (AAG) 
• Changed the PK schedule- Updated elapsed time after dose 
from 36.00 hh:mm to 30.00 hh:mm for PK sample #15. 
•  Inpatient visit time frame was changed from (Day0, Hour 0-24) 
to (Day 0, Hour 0-30) (Section 6.3) 
•  Follow-Up time frame was changed from (36 to 72 hours post-
drug administration) to (48 to 72 hours post-drug 
administration) (Section 6.4)  
• Inpatient COVID-19 tests to POC antigen rather than PCR 
• Increased the screening window from 0-10 to 0-14 days 
• Changed Safety Monitor from Dr. Mike Montana to Dr. Karan 
R. Kumar  


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• Removed COVID-19 test from Summary of Procedures under 
screening and enrollment (Section 6.1) 
• Table 5 schedule of study specific procedures was updated for 
the following timepoints: 30, 48, 72, 96 to add Vital Signs, BP, 
SpO2, Observed Sedation, MOAA/S, Thermal Pain Threshold, 
Subjective Self-Assessment, VAS. 
• Removed COVID-19 test from screening and enrollment time 
point from Summary or Procedures. 
• Revised COVID-19 footnote to indicate it should only be 
collected during the inpatient visit.  
•  Preparation and Administration was clarified adding IV bolus 
(Section 7.1.4) 
• Applied DUHS policy of re-opening guidelines to COVID-19 
testing for inpatient visit. 
• Updated time point from 24 hours to 30 hours (Sections 4.1 
and 4.3, and 6.9) 
•  Updated Maximum Blood Volumes-PK blood total from 60 mL 
to 54 mL per day. In addition, included the total amount of 
blood collected throughout the study (Section 6.8.3). 
• Added time limits for data collection timepoints 0:02 to 18:00 
hours in Table 5.  
• Specified drug infusion time. Changed from 10 minutes to IV 
push over one to two minutes 
v5.0 
31MAY2023 
• 
Created a new section which includes the risk of 
Intravenous (IV) administration (Section 2.4.2) 
• 
Added mild sedation and nausea/vomiting, Muscle spasms 
to known potential risk. Added risk for Ondansetron, ECG 
and metoclopramide (Section 2.4) 
• 
Added study procedures to study design (Section 4) 
• 
Maximum Blood Volumes-PK blood total from 54 mL to 47 
mL per day (Section 6.8.3) 
• 
Removed Section 6.7 Clinical Laboratory Evaluations 
• 
Added Section 6.7.2 Screen Laboratory Assessments 
• 
Added the following acronyms to the list of abbreviations 
table: COVID-19, MOAA/S, SpO2, TDS, and SPT 
• 
Removed CBC from Screen Laboratory Assessments 
(Section 6.7.2) 
• 
PK blood sample was updated from 3 mL to 2 mL (Section 
6.7.5) 
• 
Removed Section 6.92 Blood Collection Labs, added 
• 
Section 6.7.1 Urine Collection and Section 
• 
6.7.2 Screening laboratory assessments to provide 
clarification 


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• 
Added clarity about ondansetron and administration and 
added secondary nausea medication intravenous 
metoclopramide (Section 7.3) 
• 
Changed Data Monitoring Committee to Data Safety 
Monitoring Board (Section 8.9) 
• 
Clinical Monitoring changed DCC to STP (Section 10)  
• 
Section 2.4.2 was added to describe food and drug 
interactions. 
• 
Updated the protocol synopsis Duration of Participant 
Participation from 96 hours to 18 days to include screening 
period. 
V6.0 
27NOV2023 
• 
Increased screening window from 14 days to 30 days 
throughout the protocol, including schematic of study design 
• 
Increased total duration of participant participation from 18 
days to 34 days in the protocol synopsis to accommodate 
the updated screening period. 
• 
Based on DSMB review changed secondary outcome 
measure from “characterize the safety profile” to 
“characterize the tolerability” (Protocol Synopsis and 
Section 3) 
• 
Updated information on where screen failures should be 
recorded (Section 4.8)  
• 
Removed Small Trials Program from  List of Abbreviations 
and replaced Small Trials Program with DCRI monitoring 
team in Section 10.  
• 
Based on DSMB review, added IDS to List of Abbreviations 
• 
Based on DSMB review, included a lower limit BMI ≤17 in 
the exclusion criteria (Section 5.2) 
• 
Added parameters to exclusion criteria, specifically for 
hypercarbia and respiratory depression (Section 5.2) 
• 
Added height to the list of physical examination parameters 
collected at Screening/Enrollment visit (Section 6.2) 
• 
Removed urine drug screen abbreviations (Section 6.2) 
• 
PK samples storage temperature was changed from -80 to -
70°C (Section 6.7.4) 
• 
Updated PK Sample Timing (Table 4) 
• 
Clarified length of time pupilometer googles should be worn 
by the participant (Section 6.8.2) 
• 
Added vital sign parameters to the screening visit and 
specified that CO2 will not be collected at this visit, but all 
other vital signs (RR, HR, BP, SpO2) will be.  
• 
Clarified instructions for the thermal pain tolerance 
threshold (Section 6.8.5) 


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• 
Added +- 8 hours for the following timepoints: 48,72,96 
(Section 6.8.7) 
• 
Provided additional details to study drug Methadone 
administration method and documentation (Section 7.1.4) 
• 
Adjusted fasting period from midnight day before study-drug 
administration to food 8 hours before and liquids 4 hours 
before study drug administration (Section 7.3) 
• 
Minor administrative changes including, but not limited to, 
formatting, punctuation, grammar, abbreviations, and 
updates to table of contents 


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PROTOCOL SYNOPSIS 
Protocol Title: 
Pharmacokinetics, pharmacodynamics, and safety of a single 
dose intravenous methadone in healthy adult volunteers 
Phase: 
Phase ½ 
Study Product: 
Methadone hydrochloride 
Objectives: 
Primary:  
1. Characterize the pharmacokinetics (PK) of methadone 
hydrochloride injection 
Secondary: 
1. Characterize the pharmacodynamic effect of methadone 
hydrochloride  
2. Characterize the tolerability of methadone hydrochloride 
injection 
Exploratory:  
1. Characterize exposure-response relationships  
Study Design: 
Prospective, single-center, open-label, single-dose PK study 
Study Population: 
Healthy adult volunteers 
Number of Participants: 
Approximately 20  
Number of Sites: 
Single site 
Duration of Participant 
Participation: 
Up to 34 days 
 
 
 


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20 
CLIENT CONFIDENTIAL 
1 
KEY ROLES   
 
For questions regarding this protocol, contact: 
PTN Principal Investigator  
(IND Sponsor): 
 
Medical Monitor (MM): 
Kanecia Zimmerman, MD, PhD, MPH 
 
Karan R. Kumar, MD MS 
Duke Clinical Research Institute 
 
 Duke Clinical Research Institute 
300 West Morgan St., Durham, NC 27710 
 
300 West Morgan St., Durham, NC 27710 
Phone: +1-919-668-8651 
 
Phone: +1-919-668-0188  
Fax: +1-919-681-9457  
 
Fax: 919-681-9457 
Email: kanecia.zimmerman@duke.edu 
 
Email: karan.kumar@duke.edu 
NICHD Contract Officer Technical 
Representative (COTR): 
 
 
Perdita Taylor-Zapata, MD 
 
 
National Institutes of Health 
 
 
6710B Rockledge Drive MSC 7002 
 
 
Bethesda, MD 20892 
 
 
Phone: +1-301-496-9584 
 
 
Fax: +1-301-480-3876 
 
 
Email: taylorpe@mail.nih.gov 
 
 


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BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
Background Information  
Section 409I of the Public Health Service Act, also known as The BPCA mandates the National 
Institutes of Health (NIH) to prioritize therapeutic areas in critical need for pediatric labeling; to 
sponsor pediatric clinical trials; and to submit these data to the Food and Drug Administration 
(FDA) for consideration for labeling changes. This study will be conducted in accordance with 
Section 409I of the Public Health Service Act; as such, the results from this research may be 
submitted to the FDA for review and use in negotiated labeling changes. This research study is 
contractually supported by the Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD). The NICHD awarded a contract to Duke University (Durham, 
NC), which established a Pediatric Trials Network (PTN) Clinical Coordinating Center through its 
Duke Clinical Research Institute (DCRI) to facilitate trial design for studies supported by the 
NIH. Duke University’s Technology and Data Solutions (TDS) will oversee data management for 
the Adult Methadone project 
See ICH E6(R2) GCP, Section 6.2 (https://www.fda.gov/files/drugs/published/E6%28R2%29-
Good-Clinical-Practice--Integrated-Addendum-to-ICH-E6%28R1%29.pdf)
Background of Methadone Hydrochloride
Poorly controlled pain has been associated with notable morbidity and poor quality of life for 
both children and adults.1  
In the acute setting, such as in the post-operative period, poorly controlled pain is associated 
with delayed time to recovery, prolonged duration of opioid use, and higher healthcare costs.2
Over the long-term, persistent pain is associated with increased risk for depression or anxiety 
and difficulty working when compared to absence of pain.3 Further, pain is rated as the single 
most common reason for consulting a physician in the U.S. and may contribute to more than 
$55 billion in lost productivity for full-time workers alone.4,5
Multiple strategies have been used to treat pain, particularly in the post-operative or other acute 
settings. Opioids with fast elimination and short duration are becoming the drugs of choice for 
treatment of acute pain, often administered intravenously through patient-controlled analgesia
(repeated and frequent doses of short- and ultrashort-duration opioids), given its association 
with analgesia and patient satisfaction.6-8 However, patient controlled analgesia is generally not 
more effective than conventional opioid therapy and is associated with errors and safety 
issues.9,10  
More recent strategies have also included drugs such as methadone. In particular, methadone 
administration is increasingly common as the first-line therapy for treatment of cancer and 
neuropathic pain as well as acute post-operative pain.11,12 A single dose of methadone can 
provide analgesia for 1-2 days and provides better analgesia than conventional opioids.6,13,14
Moreover, methadone reduces further opioid requirements.6,13,14 Methadone may also prevent 
the need for hospital admissions for pain therapy, such as in vaso-occlusive crises in children 
and adults with sickle cell disease.15 Thus, methadone is an “opioid-sparing opioid.” 
Methadone’s clinical features provide a highly favorable way of minimizing opioid prescribing 
and usage to avoid addiction and overdose as well as diversion and misuse. 


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Methadone is an ideal agent for treatment of acute pain. It is an opioid analgesic, has 
repeatedly demonstrated long-acting efficacy, and is associated with reduced postoperative 
opioid requirements, less postoperative pain, and more rapid onset of effect compared to 
regimens including short-acting opioids.16,17(Table 1) Methadone also has a long elimination 
half-life, so a single dose may have long-lasting effects. Administration of the methadone is 
cost-effective, especially compared to the costs of pumps, disposables, and adverse events 
(AEs) associated with patient-controlled analgesia.6 Further, methadone has been associated 
with similar incidence of side effects compared to shorter-acting opioids.  
Table 1. Documented use of methadone in the acute setting  
Study 
Population (age) 
Comparator 
Surgery 
Results 
Murphy et al. 
201718 
120 Adults (18 – 80) 
- 63 methadone 
- 57 hydromorphone 
hydromorphone 
Spinal fusion 
Intraoperative methadone reduced 
postoperative opioid requirements, 
decreased pain scores, and 
improved patient satisfaction. 
Komen et al. 
201914 
39 Adults (18 – 65) 
- 18 methadone  
- 21 short duration 
opioid 
fentanyl, 
hydromorphone 
 
Elective same 
day surgery 
Decreased intraoperative and 
postoperative opioid requirements 
and postoperative pain resulted. 
Simoni et al. 200919 
126 Adults (18 – 65) 
- 42 methadone 
- 42 clonidine 
- 42 placebo 
clonidine, 
placebo 
Laparoscopic 
surgery 
Postoperative pain scores were 
significantly lower in the methadone 
group compared to the clonidine and 
placebo groups. 
Singhal et al. 
201620 
125 Children (mean 
age of 15) 
multimodal 
anesthesia, 
epidural with 
general 
anesthesia 
Nuss 
procedure 
Multimodal anesthesia was 
associated with decreased 
postoperative pain compared to 
general anesthesia with an epidural, 
with the group receiving methadone 
having the lowest total opioid use 
and length of stay. 
Carvalho et al. 
201821 
100 Adults (≥ 18) 
- 50 methadone 
- 50 morphine 
Morphine 
Coronary 
artery bypass 
graft 
Time to first request for analgesics 
was longer in the methadone group. 
Udelsmann et al. 
201122 
55 Adults (14 – 80) 
- 18 methadone 
- 19 morphine 
- 18 placebo 
morphine, 
placebo 
Cardiac 
surgery 
The methadone group had a longer 
time until first request for analgesia, 
lower use of analgesia, and higher 
quality of analgesia compared to 
morphine and placebo without 
difference in time to extubated. 
Russell et al. 
201323 
75 Adult women  
- 25 methadone 
- 50 control 
fentanyl, 
morphine, 
fentanyl and 
morphine 
Caesarean 
delivery 
The methadone group had lower 
pain scores and decreased opioid 
requirements immediately 
postoperatively, as well as 
decreased opioid use over 48 hours. 
Gottschalk et al. 
201124 
30 Adults (18 – 75) 
- 13 methadone 
Sufentanil 
Spinal fusion 
The methadone group had 
decreased pain scores at 48 hours 


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- 16 sufentanil 
and decreased opioid usage at 48 
hours compared to the sufentanil 
group . 
 
Methadone was, however, developed and approved long before the regulatory requirements for 
pharmacokinetic (PK) and pharmacodynamic (PD) characterizations and numerous in vitro and 
in vivo preclinical and clinical studies, which are required today for drug approvals. While some 
investigations in the past few years have discovered missing information regarding methadone 
biotransformation, drug interactions, and genetics,25-27 much fundamental information about 
methadone PK and PD remains missing. In addition, far more is known about the pharmacology 
of oral methadone used in high doses for the treatment of opioid addiction (80-160 mg daily) 
than about smaller intravenous doses used for acute pain (5-10 mg).   
Based on known information, methadone, is clinically used as a racemic mixture, with R-
methadone acting on the mu receptor, while both R- and S-methadone act to antagonize N-
methyl-D-aspartate receptors.28 The drug is lipophilic and has linear PK with a steady state 
volume of distribution ranging from 2-6 L/kg. Methadone is also 85-90% protein bound in 
plasma, primarily to alpha1-acid glycoprotein. Metabolism of methadone primarily occurs via 
CYP2B6 N-demethylation to inactive metabolites, primarily ethylidene-1,5-dimethyl-3,3-
diphenylpyrrolidene (EDDP).25 Methadone has a highly variable clearance, ranging from 3-10 
L/h, and a terminal half-life of 8-59 hours. However, methadone persists in the liver and other 
tissues, with slow release sometimes resulting in prolonged duration of action.29  
Because of its potential prolonged duration of action, labeled dosing of intravenous (IV) 
methadone for use in opioid non-tolerant patients is 2.5-10 mg every 8-12 hours, slowly titrated 
to effect. Available data on methadone PK during treatment of acute pain are listed in Table 2.  
Table 2. Methadone PK during treatment of acute pain 
Study 
Population (age) 
Route 
Dose 
Substrate 
Results  
Horst  
et al. 
201615 
24 Adolescents (7 – 17) 
- 12 methadone 
- 12 control 
23 Adults (18 – 55) 
- 11 methadone 
- 12 control 
IV 
 
0.1 – 0.125 mg/kg 
Venous blood 
Methadone and EDDP 
concentrations and PK in 
children with sickle cell disease 
was comparable to those in 
children and adults receiving 
surgery. 
Sharma  
et al. 
201130 
31 Children (5 – 18) 
 
IV 
0.1mg/kg (10 children) 
 
0.2mg/kg (10 children) 
 
0.3mg/kg (11 children)  
Venous blood 
Methadone did not affect 
postoperative pain scores and 
did not decrease daily or total 
postoperative opioid 
consumption. 
Stemland 
et al. 
201231 
17 Adolescents (12 – 
19) 
IV 
0.25 mg/kg 
Arterial blood 
PK of methadone in adolescents 
is similar to those reported in 
adults. 
Meissner 
et al. 
201432 
16 Adults (18 – 40) 
IV and 
Oral 
 
IV: 5 mg/kg over 2 
hours 
 
Venous 
plasma, and 
urine 
Cyclosporine did not affect 
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Oral: 4.5 mg/kg twice 
daily for 4 days
Kharasch 
et al. 
201525
64  Adults (18 – 50) 
IV and 
Oral
IV: 6 mg/kg
Oral: 11 mg/kg
Venous 
plasma, and 
urine
Methadone plasma 
concentrations were influenced 
by CYP2B6 polymorphisms, oral 
was affected more than 
intravenous, and S- more than 
R-methadone.
The influence of age on methadone PK is unknown. Also, no label information exists on the PK 
or PD of methadone in children (< 18 yr). Nonetheless, methadone is widely used in children, 
such as to treat neonatal abstinence syndrome and as an intraoperative and postoperative 
analgesic. From a perioperative perspective, more than 500,000 inpatient operations are 
performed on children, and several times that many outpatient operations. Thus, a significant 
opportunity exists to improve the clinical evidence informing the use of methadone, and 
specifically, the unmet need for a better understanding of methadone PK and PD across all age 
groups. 
Adult Labeling of Methadone Hydrochloride  
Methadone currently has the following labeled indications: 
•
For the treatment of moderate-to-severe pain not responsive to non-narcotic 
analgesics.
•
For use in temporary treatment of opioid dependence in patients unable to take oral 
medication.
Methadone PKs have not been evaluated in children, nor is methadone approved for use in 
children. 
Scientific Rationale 
Identifying the PK/PD relationship for IV methadone in adults is essential to determining optimal 
dosing and understanding variation in drug disposition. Further, establishing this relationship will 
lay the foundation for labeling methadone in children with acute pain. 
Potential Benefits
There is no expected benefit to the healthy volunteers who participate in this study. However, 
data from this study will provide benefits to adults and children in the future.
Known Potential Risks
Methadone administration is associated with the following risks: 
•
Mild sedation (being in a relaxed, calm state)
•
Nausea and/or vomiting
•
Addiction, Abuse, and Misuse 
•
Life Threatening Respiratory Depression 
•
QTc Prolongation 


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•
Interactions with central nervous system Depressants 
•
Serotonin Syndrome 
•
Adrenal Insufficiency 
•
Severe Hypotension
•
Gastrointestinal Adverse Reactions 
•
Seizures 
•
Withdrawal 
•
Spasm of muscles
The major hazards of methadone are respiratory depression and systemic hypotension, though 
to a lesser degree. Additionally, respiratory arrest, shock, cardiac arrest, and death have 
occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, 
sedation, nausea, vomiting, and sweating.33
Risks will be minimized using standard procedures of the DEPRU. Briefly, participants will be 
monitored by trained nursing personnel and have direct access to emergency services 
throughout the study duration. Additionally, DEPRU has a crash cart, each participant room is 
equipped with oxygen, and naloxone can be requested to be at the bedside.
Ondansetron will be administered to help prevent nausea and vomiting. Ondansetron can cause 
headache and in extremely rare cases severe allergic reaction.
Metoclopramide will be administered if ondansetron is not effective in preventing nausea and 
vomiting. Metoclopramide can cause tardive dyskinesia, neurological effects, gastrointestinal 
effects, cardiovascular effects and mental health effects. Metoclopramide may have reduced 
efficacy in the presence of methadone.
Electrocardiogram (ECG) will be administered to detect possible QTc Prolongation. The ECG 
may cause skin irritation, itching, and redness from the ECG electrode pads.
Thermal stimulation, which will be used to assess methadone PD, includes a slight risk of a 
burn, but this is minimized by (a) positive lockout of stimulus parameters above 53°C and (b) a 
built-in shut-down system to prevent the delivery of prolonged or high-intensity stimuli. 
Biological specimens will not be collected if, in the opinion of the investigator, collection is 
determined potentially harmful to the participant.
Any condition that would make the participant, in the opinion of the investigator, unsuitable for 
the study, will preclude the participant from being enrolled into this study.
Risks of Blood Drawing
The participant may feel discomfort, dizzy, or light-headed during the blood draw. Where the 
needle enters the skin, bruising, swelling, or bleeding are possible. Every effort will be made to 
use existing indwelling lines for blood sampling.
The total participant blood volume drawn will not exceed the maximum blood volume allowed for 
the study period (see Section 6.7.5).


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Risk of Drug and Food Interactions 
The participant must tell the study doctor or nurse about all the prescribed medical foods and 
drugs, herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol
they are taking before starting the study. In addition, participants should let the study staff know 
of any changes in medications or new products you start taking during the study.
Risk of Intravenous (IV) Infusion and Taking Blood from IV
The study drug is administered through an IV catheter which is a small, flexible hollow tube 
inserted into a vein in the arm.  Inserting an IV requires a needle and can cause localized 
discomfort. The vein the catheter is inserted in may become inflamed with signs of redness and 
warmth at or near the IV insertion site. Inflammation in a vein due to a blood clot is also a 
potential risk. In some instances, the vein may develop a small rupture causing the drug to leak 
out of the vein. This is generally not dangerous, but can cause discomfort and bruising.  There 
is a risk of infection; however, this is a small risk as aseptic technique will be used. Blood 
samples will be drawn from an IV. The potential risk related to this are: risk of infection into the 
bloodstream during blood draw procedure, pain or discomfort, inflammation of the vein known 
as phlebitis, and bruising at injection site.
Potential Risk of Loss of Confidentiality
Loss of confidentiality is a potential risk. Every effort will be made to protect the participant’s
confidential medical information, but this cannot be guaranteed. 
Pregnancy Risks
Pregnancy is an exclusion for this study. Risks for pregnant women can be found in the 
methadone hydrochloride product label.33
Unforeseen Risks
This research may present other risks to the participant that are not known or foreseeable at this 
time. 


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3 
OBJECTIVES AND OUTCOME MEASURES 
 
Objective 
Measures 
Endpoints 
Primary 
Characterize the PK 
of methadone 
hydrochloride 
injection 
Plasma concentrations 
1. Clearance (CL)  
2. Volume of distribution (Vz)  
3. Half-life (t1/2) 
4. Area under the curve (AUC) 
5. Maximum concentration 
(Cmax) 
6. Time to maximum 
concentration (Tmax) 
7. Minimum concentration 
(Cmin) 
8. Elimination rate constant (ke) 
Secondary 
Characterize the PD 
effect of methadone 
hydrochloride 
injection  
1. Dark-adapted pupillometry 
2. Observed sedation 
3. Thermal pain tolerance 
thresholds 
4. Subjective self-assessment 
of methadone effects using 
visual analog scale (VAS) 
Change in pupillometry, 
observed sedation, thermal pain 
tolerance thresholds, and VAS 
from pre-dose to each post-dose 
time point 
Secondary 
Characterize the 
tolerability of 
methadone 
hydrochloride 
injection  
1. Adverse events (AEs) 
2. Serious adverse events 
(SAEs) 
3. Suspected Unexpected 
Serious Adverse Reactions 
(SUSARs) 
4. Safety events of special 
interest (QTc) 
For AEs, SAEs, SUSARs: 
Proportion of participants from 
baseline to the end of safety 
follow-up 
 
For SESI: Change in QTc from 
baseline to the end of safety 
follow-up 
Exploratory Characterize 
exposure-response 
relationships  
Plasma concentrations and 
VAS 
Correlation of plasma 
concentrations to VAS score at 
each post-dose VAS time point 
 
 
 
 


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4
STUDY DESIGN
Study Design
The trial aims to investigate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of 
intravenous (IV) methadone hydrochloride in approximately 20 healthy adults. Eligible 
participants who have followed fasting and dietary requirements will be admitted to the Duke 
Early Phase Research Unit (DEPRU) for a single study-drug/methadone infusion and PK blood 
draws. The inpatient stay duration will be approximately 30 hours. Various assessments will be 
conducted from the inpatient visit to the final study visit, including: pupil diameter measurement, 
vital sign collection, Modified Observer's Assessment of Alertness and Sedation (MOAA/S),
which measures sedation level evaluation, thermal pain tolerance assessment, subjective self-
assessment using the Visual Analog Scale (VAS), Electrocardiogram (ECG) and safety 
evaluations. After discharge, participants will be asked to return to clinic at various time points 
over the subsequent 96 hours to provide blood samples for PK analysis and complete the 
various study procedures. 
Study intervention: Single-dose trial of IV methadone hydrochloride
Study procedures: Pupillometry, vital sign collection, MOAA/S, thermal pain tolerance, ECG,
VAS
Duration of participant participation: Up to 4 days after study enrollment, including up to 30 days 
for screening.
Biological specimen collection: Blood for PK, blood for pregnancy testing, urine for drug 
screening, breathalyzer, urine for pregnancy testing
Biological specimen retention plan: See Section 12
Study Product or Intervention
Rationale for Dose Selection
The administered dose of 0.1 mg/kg methadone hydrochloride is the labeled dose for the 
treatment of pain in adults. The goal of this study is to better understand the PK of this labeled 
dose. 
Duration of Participant Participation
The screening visit will occur 0-30 days prior to study start. From time of consent, participation 
may be up to 96 ± 8 hours after study drug administration, wherein the first 30 hours is an 
inpatient visit, including study drug administration and PK blood draws, followed by a 48 hour, 
and 72-hour follow-up. The final visit will occur at 96 hours.
Biological Specimen Collection  
Blood samples will be collected from participants for PK analysis. 


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DOI-specific Testing
Blood samples obtained during the study will be analyzed for plasma concentrations of 
methadone and a methadone metabolite, EDDP, using a validated liquid chromatography with 
tandem mass spectrometry assay under Good Laboratory Practice conditions.
Events of Special Interest
Safety ESIs
Safety ESI includes QTc interval (ECG). 
Efficacy ESIs
Efficacy ESIs include the following: 
•
miosis (dark-adapted pupillometry) 
•
ventilation (respiratory rate (RR), end-tidal expired CO2)
•
analgesia (thermal pain tolerance thresholds, VAS responses to methadone, self-
reported assessments)
Study Definition of Enrollment
Study Definition of Enrollment into Active Study
Study enrollment is defined as a participant providing informed consent and receiving IV
methadone.
Screen Failures
A participant will be considered a screen failure if he or she provided informed consent but did
not receive IV methadone. This screen failure will be recorded on the disposition form in the 
EDC under “Did Participant Receive Study Drug?
Study Definition of Completion
Participant Completion*
A participant will be considered complete if he or she received the single dose of IV methadone 
and was followed for safety through the last follow-up visit.
Study Completion 
The study will be considered complete when all participants have completed the final visit and 
all required study and follow-up assessments.
*Participants not satisfying the above criteria for study completion will be reported as early 
terminators in the data system.


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5
STUDY POPULATION
Selection of the Study Population/Sample Size
Approximately 20 evaluable healthy volunteers 18 to < 40 years old will be enrolled. Sex will be 
approximately equally distributed. Participants will be recruited from the greater Durham and 
Triangle community and a healthy volunteer registry in the DEPRU. Participants will be 
compensated.
Inclusion/Exclusion Criteria
Inclusion 
Criteria
1. 18 to < 40 years of age at the time of enrollment
2. Provides informed consent
Exclusion 
Criteria
1. History of cardiac dysfunction 
2. History of or current QTc prolongation, defined as > 470 ms in males and > 
480 ms in females
3. Known hypersensitivity to methadone hydrochloride or any other ingredient 
in the methadone hydrochloride injection
4. Known acute bronchial asthma or hypercarbia (history of known PaCO2
above 45 mm HG)
5. Receipt of a serotonergic drug or bupropion within 7 days prior to study 
enrollment 
6. Receipt of benzodiazepines, muscle relaxants, or other opioids within 7 
days prior to study enrollment
7. Receipt of a moderate or strong CYP2B6 inhibitor or inducer – either
prescription or non-prescription medications, herbals,34 or foods known to 
be metabolized by or affecting CYP2B6 within 30 days prior to study 
enrollment
a) CYP2B6 inhibitors include clopidogrel, prasugrel, thioTEPA, ticlopidine, 
voriconazole, macrolide antibiotics, azole-antifungal agents, 
fluconazole, Alstonia boonei, Mangifera indica, and Picralima nitida
b) CYP2B6 inducers include artemisinin antimalarials, barbiturates, 
carbamazepine, cyclophosphamide, efavirenz, lopinavir, methimazole, 
nelfinavir, phenobarbital, phenytoin, primidone, rifampicin/rifampin, 
ritonavir, abacavir, amprenavir, nevirapine, telaprevir
8. Receipt of zidovudine, desipramine, or other drugs that may increase 
serum concentration when combined with methadone within 30 days prior 
to study enrollment
9. Known or suspected gastrointestinal obstruction, including paralytic ileus
10. Significant respiratory depression (respiratory rate less than 8 breaths/min 
or oxygen saturation (SpO2) <95%)
11. BMI ≥ 33 and BMI ≤17
12. Known history of moderate-to-severe liver (Child Class B or C) or kidney 
disease (serum creatinine > 1.5)
13. Known history of drug or alcohol addiction (prior or present addiction or 
treatment for addiction)
14. Females who are pregnant or nursing


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Participant Discontinuation/Withdrawal
Participant Decides to Withdraw Consent
A participant may voluntarily withdraw consent to participate in the study at any time. No 
additional study procedures or data will be collected after consent has been withdrawn; 
however, all data and specimens collected up to the point of consent withdrawal will be 
maintained. The participant will be marked as early terminated from the study. The reasons for 
withdrawal, or failure to provide a reason, must be documented by the investigator. The 
participant is not obligated to state the reason for withdrawal.
Participant Decides to Withdraw from Study Intervention
A participant may choose to withdraw from the study intervention during or after receiving 
methadone for any reason but continue to be followed for all study assessments. The reasons 
for withdrawal from study intervention, or failure to provide a reason, must be documented by 
the investigator. The participant is not obligated to state the reason for withdrawal. 
Study Investigator/Sponsor Decides to Withdraw Participant
The Study Principal Investigator (PI) or IND sponsor (i.e., a study authority) may withdraw a 
participant without consent if the following occurs: 
•
The participant’s condition changes or a safety event occurs while on study, and the 
study is no longer in his or her best interest; 
•
The participant is non-compliant with the study protocol; or
•
The entire study is stopped by the FDA, the sponsor, or other applicable party. 
A participant who is discontinued from methadone due to an AE, whether serious or non-
serious, must be followed by the investigator until the AE is resolved or considered stable. The 
medical monitor (MM) or Study PI must be notified if the AE possibly relates to methadone 
overdose. The package insert should be consulted for details of any specific actions to be taken 
(link to package insert).29  
If any of the above occurs, the participant will be informed of the withdrawal, and the 
investigator will discuss other options.
Replacements
In cases of early withdrawal from study, study dosing, or procedures – defined as a participant 
who has had < 5 specimens obtained – either by the participant or study authority, a 
replacement participant may be enrolled. 


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6
STUDY PROCEDURES
Summary of Procedures
Table 3. Schedule of study procedures and assessments
Screening/
Enrollment
Inpatient 
Visit
Follow Up Visits
Final 
Study Visit
Early 
Withdrawal 
Visit
PROCEDURE
Day -30 to 0
Day 0,
Hour 0 - 30
Hour
48 ± 8
Hour
72 ± 8
Hour
96 ± 8
Informed consent
X
Confirm eligibility criteria
X
Demographics
X
Physical examination
X
Medical history
X
Concomitant medications
X
X
X
X
X
Pregnancy test 
X
X1
COVID-19 test2
X2
Blood collection3
X
X3
X
X
X
X
Drug and alcohol screen
X
X
Electrocardiogram
X
X
X
Pupillometry
X5
X
X
X
Vital signs4
X
X5
X
X
X
Observed sedation, 
MOAA/S
X5
X
X
X
Thermal pain tolerance
X5
X
X
X
Subjective self-assessment, 
VAS
X5
X
X
X
Study drug administration
X
Safety events
X
X
X
X
X
1 Serum quantitative testing will occur at screening and urine qualitative (point of care) testing will occur at the start of 
the in-patient visit. 
2 Per DUHS policy, COVID-19 testing may occur if the participant presents with new onset symptoms of COVID-19 or 
has had COVID-19 exposure within the last ten days. 
3 See Sections 6.7.2.(labs at Screening/Enrollment) and 6.7.4 (PK at Day 0) for details regarding blood sample 
collection times.
4 Vital signs collected at enrollment: respiration rate (RR), heart rate (HR), blood pressure (BP), and oxygen 
saturation (SpO2). Vital signs collected at 30,48,72 and 96 hours: RR, carbon dioxide (CO2), HR, BP, and SpO2. See 
Section 6.8.3 for details. 
5 See Table 5 for details regarding collection times.


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Screening/Enrollment (Day -30 to 0)
The investigator will screen participants according to the eligibility criteria (Section 5.2). 
Screening must remain impartial (no selectivity) to prevent bias.
Potential candidates’ eligibility must be confirmed, or re-confirmed, and documented in the 
source records by the Study PI (or designee), prior to the conduct of any study procedures. 
Potential candidates will be educated on the study procedures, benefits, and potential risks as 
part of the applicable informed consent. Following consent, the enrolled participant’s 
demographic information will be recorded, and the participant will undergo the following:
•
Physical examination, including capturing weight and height
•
Vital signs (heart rate, blood pressure, respiratory rate and oxygen saturation)
•
Medical history
•
ECG to determine QTc
•
Review of concomitant medications
•
Blood collection for clinical laboratory assessments (Section 6.7.2)
•
Serum quantitative pregnancy test
•
Urine drug screen to test for illegal and prescription drugs
o
Methamphetamine 
o
Morphine-a drug in the opiate class 
o
Marijuana 
o
Amphetamine 
o
Barbiturates 
o
Benzodiazepines
o
Cocaine
o
Phencyclidine 
o
Methadone 
o
Ecstasy/MDMA 
•
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For alcohol and substance abuse, the study team will query the potential participant about past 
and current drug and alcohol use or treatment of use, then document said testimony, which will 
be validated by the urine drug screen and breathalyzer.
This visit will occur up to 30 days before the inpatient visit to allow adequate time for the return 
of clinical laboratory results. 
Refer to MOP for details.
Inpatient Visit (Day 0, Hour 0 - 30)
The study day will consist of an approximately 30-hour stay for participants in the DEPRU for 
methadone administration, blood sampling, and PD assessments. Abstinence requirements are 
listed in Section 7.3. The following will occur at the inpatient visit:
•
Rapid COVID-19 test will occur per the DUHS policy if the participant presents with new 
onset symptoms of COVID-19, or reports COVID exposure within the last ten days, 
•
Urine qualitative pregnancy test
•
Review of concomitant medications
•
Urine drug screen and breathalyzer
•
Blood collection for PK analysis (see Section 6.7.4 for timing of blood draw)
•
Electrocardiogram for QTc, prior to study drug administration and 30 hours after study 
drug administration 
•
Pupillometry, goggles for dark-adapted pupil diameter
•
Vital signs, including RR, end-expired CO2, HR, BP, and SpO2
•
Observed sedation, MOAA/S
•
Thermal pain tolerance threshold
•
Subjective self-assessment, VAS
•
Methadone hydrochloride administration
•
Safety event assessment
Participants will be free to move around and be given a standard meal 4 hours after completion 
of methadone hydrochloride administration. Thereafter, participants will have free access to 
food and water while in the DEPRU. After the inpatient visit, participants should be transported 
home by a person previously arranged by the participant. 


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Follow-Up (48 to 72 hours post-drug administration)
At approximately 48, and 72 ± 8 hours after methadone administration, participants will return to 
the DEPRU for the following procedures:
•
Review of concomitant medications
•
Blood collection for PK analysis 
•
Pupillometry, goggles for dark-adapted pupil diameter
•
Vital signs, including RR, end-expired CO2, HR, BP, and SpO2
•
Observed sedation, MOAA/S
•
Thermal pain tolerance threshold
•
Subjective self-assessment, VAS
•
Safety event assessment
Final Study Visit (96 hours post-drug administration)
At approximately 96 ± 8 hours after methadone administration, the final study visit will be in-
person at the DEPRU and include the following: 
•
Review of concomitant medications
•
Blood collection for PK analysis 
•
Electrocardiogram for QTc
•
Pupillometry, goggles for dark-adapted pupil diameter
•
Vital signs, including RR, end-expired CO2, HR, BP, and SpO2
•
Observed sedation, MOAA/S
•
Thermal pain tolerance threshold
•
Subjective self-assessment, VAS
•
Safety event assessment
Early Study Withdrawal Visit
In the event the participant chooses to terminate the study early, an early study withdrawal visit 
will include the following:
•
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•
Safety event assessment
Specimen Collection for Study-Specific Tests
Refer to MOP for details. 
Urine Collection
Urine will be collected for all participants at the screening visit to assess for illegal drugs. Urine 
will be collected from females of child-bearing potential at the inpatient visit for pregnancy 
status.
Screening laboratory assessments
Blood will be collected at the screening visit for the following assessments: serum pregnancy 
test (for females of child-bearing potential and CMP (complete metabolic panel). Fasting is not 
required. The CMP will be used to assess for exclusion criteria for those for known history of 
moderate-to-severe liver (Child Class B or C) or kidney disease (serum creatinine > 1.5).   
Pharmacokinetic Tests   
Blood specimens for methadone PK will be collected per the schedule in Table 4. 
PK Sampling Schedule   
The total number of PK blood samples will be 18, 2 ml/sample, 36 ml (less than one-quarter
cup). Blood will be centrifuged and plasma removed and stored at -70°C until shipment to a 
laboratory for analysis. The time of each sample collection should be recorded. 
Table 4. Optimal PK sampling schedule relative to single dose of methadone
PK Time Point Sample Number
Elapsed Time After Dose (hh:mm)
1
  Baseline draw
Start IV dose
methadone HCl 0.1 mg/kg bw
2
   0:00 + 0:011
IV push over 1 -2 minutes
(including 3ml 0.9NS flush 
immediately following study 
medication administration 
3
  0:05 ± 0:01
4
    0:10 ± 0:01
5
  0:15 ± 0:01
6
  0:30 ± 0:05
7
1:00 ± 0:10
8
  1:30 ± 0:10
9
  2:00 ± 0:10
10
   4:00 ± 0:302
11
  6:00 ± 0:30
12
12:00 ± 0:30
13
18:00 ± 0:30
14
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1Immediately after starting IV dose
2Food can be served after the 4:00 sample collection.
Maximum Blood Volumes 
The maximum volume of fresh/non-scavenged whole blood to be collected is approximately 
47 mL (equivalent to 3.2 tablespoons). A maximum of 18 blood samples of 2 mLs each can be 
obtained for each PK sample. A total of 8 mLs will be collected for on-site laboratory test: HCG 
(3.5 mLs and CMP 4.5 mLs). This total volume also includes a small amount of additional blood
(3 mL) that is discarded prior to collecting each PK sample. 
 Study-specific Procedures
Electrocardiogram
A 5- or 12-lead ECG will acquire QTc prior to study drug administration screening, 30 and 96 
hours after study drug administration. 
Refer to MOP for details. 
Pupillometry, Dark-Adapted
Dark-adapted pupillometry will measure pupil diameter using a goggle-based, camera-like 
device (I-Portal® Falcon, https://www.neurolign.com/products/#hardware). A goggle-based 
system effectively allows the participant to be in the dark while room lights are on for research 
staff. The participant will wear the goggles continuously for the first hour of PK sampling. 
Thereafter, the goggles can be removed. See Table 5 for details when this measurement 
should be completed. 
Refer to MOP for details.
Vital Signs 
Vital signs collected at screening include: RR, HR, BP, and SpO2. Vital signs collected at 
30,48,72 and 96 hours include RR, CO2, HR, BP, SpO2. Respiratory rate and end-expired CO2
concentration are recorded using Medtronic Capnostream monitor with FilterLine sampling lines 
(https://www.medtronic.com/covidien/en-us/products/capnography/capnostream-20p-bedside-
patient-monitor.html (https://www.medtronic.com/covidien/en-us/products/capnography/filterline-
etco2-sampling-lines.html). 
Refer to MOP for details. 
Observed Sedation, MOAA/S  
Sedation will be observed and recorded by the study team using the Modified Observer’s 
Assessment of Alertness/Sedation (MOAA/S).  
15
30:00 ± 1:00
16
48:00 ± 8:00
17
72:00 ± 8:00
18
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Modified Observer’s Assessment of Alertness/Sedation [MOAA/S]
Responsiveness
Score
Responds readily to name spoken in normal tone
5 (alert)
Lethargic response to name spoken in normal tone
4
Responds only after name is called loudly and/ or repeatedly
3
Responds only after mild prodding or shaking
2
Responds only after painful trapezius squeeze
1
Does not respond to painful trapezius squeeze
0
Refer to MOP for details. 
 Thermal Pain Tolerance Threshold  
Thermal pain tolerance will be measured by a 3 cm2 computer-controlled Peltier-type thermal 
stimulator (Pathway; Medoc Advanced Medical Systems, https://medoc-
web.com/products/pathway-model-ats/ or similar thermal stimulator). The stimulator delivers
painful heat stimuli to the volar side of the forearm. Before any stimulus is applied, participants 
are familiarized with the test procedure and instructed on how to evaluate their pain. Pain is 
evaluated using a standard verbal scale from 0 (no pain) to 100 (worst possible pain). 
The thermode system’s baseline temperature is set at 32°C. The computer-controlled thermode 
system is programmed to gradually increase the stimulus (0.8°C/sec) until participants press a 
stop button, which indicates maximum tolerable temperature was reached and initiates 
immediate thermode cooling. The maximum tolerable temperature is recorded. 
The thermode system’s maximum temperature is set to 52°C to prevent thermal injury. If the 
thermode reaches 52°C without the participant pressing the button, then temperature increase 
ceases and immediate thermode cooling is initiated, and 52°C is recorded as the maximum 
tolerable temperature. 
The maximum temperature testing is repeated three times for each time event, as the probe is
moved and cooled between each stimuli, the averages of the three maximum temperatures and 
pain ratings are recorded,. The primary outcome measure is the average maximum tolerable 
temperature.
Refer to MOP for details.
Subjective Self-assessment  
Each participant will use a VAS to indicate levels of alertness/sedation (almost asleep to wide 
awake), energy level (no energy to full of energy), confusion (confused to clear headed), 
clumsiness (extremely clumsy to well-coordinated), anxiety (calm/relaxed to extremely nervous), 
and nausea (no nausea to worst nausea), each on a score of 0 to 100. Alternatively, plastic 
sliders may be used (http://www.custompromotionalrulers.com/visual-analog-scale-vas-
rulers/vas-pain-scale-rulers-0-10-cm-w/buckle-slider/ or similar), which are then scored from 0 to 
100.
1. Please rate how awake you feel: 0 (asleep) - 100 (wide awake)


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2. Please rate your level of energy: 0 (no energy) - 100 (full of energy)
3. Please rate how confused you feel: 0 (clear headed) - 100 (extremely confused)
4. Please rate how clumsy you feel: 0 (well-coordinated) - 100 (extremely clumsy)
5. Please rate how anxious you feel: 0 (totally relaxed) - 100 (extremely nervous)
6. Please rate if you feel nauseated: 0 (no nausea) - 100 (worst nausea)
Summary of Study-specific Procedures
Table 5. Schedule of study-specific procedures
Elapsed Time 
After Dose 
(hh:mm)
Pupillometry, 
Dark-Adapted
Vital Signs
RR, CO2, HR
Vital Signs
BP, SpO2
Observed 
Sedation, 
MOAA/S
Thermal Pain 
Threshold
Subjective Self 
Assessment, 
VAS
Baseline draw
X
X
X
X
X
X
Start IV dose
0:02 ± 0:01
X
X
X
0:04 ± 0:01
X
X
X
X
0:06 ± 0:01
X
X
X
0:08 ± 0:01
X
X
0:10 ± 0:01
X
X
X
X
X
X
0:12 ± 0:01
X
X
0:15 ± 0:01
X
X
0:20 ± 0:01
X
X
0:30 ± 0:02
X
X
0:40 ± 0:02
X
X
X
X
X
0:50 ± 0:02
X
X
1:00 ± 0:05
X
X
X
X
X
X
1:30 ± 0:05
X
X
X
2:00 ± 0:10
X
X
X
X
X
X
3:00 ± 0:10
X
X
X
4:00 ± 0:10
X
X
X
X
X
X
6:00 ± 0:30
X
X
X
X
8:00 ± 0:30
X
X
X
X
X
10:00 ± 0:30
X
X
X
12:00 ± 0:30
X
X
X
X
X
X
18:00 ± 0:30
24:00 ± 1:00
X
X
X
X
X
30:00 ± 1:00
X
X
X
X
X
X
48:00 ± 8:00
X
X
X
X
X
X
72:00 ± 8:00
X
X
X
X
X
X
96:00 ± 8:00
X
X
X
X
X
X


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Some timepoints have multiple tasks scheduled. It is suggested that the tasks be prioritized in 
order of: obtaining the PK sample, pupillometry, vital signs, observed sedation. thermal pain 
threshold, and subjective self-assessment. These tasks are not all performed during all the 
timepoints, please follow Tables 4 and 5 above. The research staff does have the discretion to 
perform the task order according to their trained judgement as long as they are within the 
timepoint parameters.
Study-specific PK Specimen Preparation, Handling, Storage, and 
Shipping
Biological samples collected for the purposes of this research will be labeled only with a unique 
accession number (via study-provided barcode label) without protected health information (PHI) 
that can directly identify the study participant. These samples will be sent to the PTN-designated 
laboratory for analysis (i.e., methadone concentration measurements). Once samples are 
analyzed, data will be entered into the study records. After all study-related testing is complete,
any remaining samples will be shipped to an NIH-designated biorepository for future unspecified 
use, unless prohibited by local ethics committee or regulatory agencies (see Section 12). 
Refer to the MOP for instructions for the collection, labeling, preparation, handling, and storage 
of specimens.


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7
STUDY PRODUCT DESCRIPTION
Study Product Information 
Methadone hydrochloride is a mu-agonist; a synthetic opioid with multiple actions qualitatively 
similar to those of morphine. The most prominent action involves the central nervous system 
and organs composed of smooth muscle. Methadone’s principal therapeutic uses are for 
analgesia and for detoxification or maintenance in opioid addiction. Specific PK and PD qualities 
of methadone are in the FDA drug label.29
Dosage and Dose Timing 
Each participant will be administered a single dose of IV methadone at 0.1 mg/kg per measured 
body weight. The single dose will be calculated to the closest 0.1 mg.
Formulation, Packaging, and Labeling 
Methadone Hydrochloride Injection USP, 10 mg/mL from Mylan Institutional LLC will be used for 
this study.33 It is supplied as 20-mL multi-dose vials. Each mL of Methadone Hydrochloride 
Injection USP contains 10 mg (0.029 mmol) of methadone hydrochloride. The injectable solution 
contains the following inactive ingredients: chlorobutanol, 0.5%, as a preservative, and sodium 
chloride. 
Refer to MOP for details.
Product Storage and Stability 
Methadone Hydrochloride Injection USP should be stored at 20 to 25°C (68 to 77°F), with 
excursions permitted between 15 to 30°C (59 to 86°F). It should be protected from light and 
stored in carton until contents have been used. 
Refer to MOP for details.
Preparation and Administration
Methadone will be prepared by Duke Investigation Drug Services (IDS). Each participant will 
receive 0.1 mg of methadone per kg of body weight from the 10 mg/mL stock concentration
administered via IV push. Methadone (0.1mg/kg bw) will be administered via IV push followed 
by 3mL flush over 2 minutes. The time IV push begins and the time flush ends will be 
documented on the source. 
Refer to MOP for details. 
Accountability Procedures for the Study Product
Methadone hydrochloride will be prepared by Duke Investigational Drug Services and 
administered intravenously to participants by study nurses. 
Refer to MOP for details.


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Replacement Doses
If the product dose is broken or unusable, study personnel will prepare study product from a 
new vial. Replacement doses may be requested by contacting the Duke Investigational Drug 
Services.
See MOP for contact information.
Disposition of Study Products Upon Study Completion or Expiration
Upon completion of the study, or upon notice of the study products’ expiration, the study 
products should be disposed of at the site, pursuant to the ICH/GCP guidelines and the Duke 
Investigational Drug Services policy for drug destruction. 
See MOP for details. 
Concomitant Medications/Treatment Restrictions
Participants should not receive serotonergic drugs within 7 days prior to drug administration or 
during treatment or follow-up period (up to 96 hours). Participants should not receive inhibitors 
or inducers of CYP2B6 within 30 days prior to enrollment or during the study period. See 
Section 5.2 for a listing. 
Participants will be required to abstain from the following: 
•
30 days before study-drug administration: non-study medications (including over the 
counter and/or herbal), without prior PI approval – non-study medications that are given 
per standard of care and are not exclusionary will receive approval, at the discretion of 
the Study PI.
•
24 hours before study-drug administration and during study days: alcohol 
•
8 hours before study-drug administration: food 
•
4 hours before study-drug administration: liquids 
•
Day of administration: alcohol and caffeine
Current substance or drug dependence will be confirmed by positive urine drug screen at the 
screening/enrollment visit. Current alcohol abuse will be confirmed by positive breathalyzer at 
the screening/enrollment visit.
Ondansetron (4 mg IV) will be administered 15 minutes prior to methadone administration to 
decrease or prevent nausea. If initial dose is not efficacious, and nausea persists, intravenous 
metoclopramide (10 mg) will be provided.
The date, time, route, and dose of all concomitant medications of interest will be recorded.


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8
ASSESSMENT OF SAFETY
Specification of Safety Parameters
Studies performed under IND FDA regulations require reporting based on the definition included 
in 21 CFR 312.32 (a), regardless of the definition of AE used in the protocol.
An adverse event (AE) is any untoward medical occurrence in humans, whether or not 
considered intervention-related, which occurs during the conduct of a clinical trial. (Any change 
in clinical status, ECGs, routine labs, x-rays, physical examinations, etc., that is considered 
clinically significant by the Study PI is considered an AE). 
An unexpected adverse event is any AE, of which the nature, specificity, or severity is not 
consistent with the applicable product information (e.g., package insert/approved label) or 
investigational plan.
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that 
the intervention caused the AE. A reasonable possibility implies that there is evidence that the 
intervention caused the event. 
An adverse reaction (AR) is any AE caused by the intervention. 
A serious, unexpected, suspected adverse reaction (SUSAR) is a SAR that is both serious 
and unexpected. 
All AEs related to methadone administration will be reported. Safety will be assessed by 
frequency and incidence of reported AEs, SAEs, and SUSARs. A safety Data Monitoring Safety 
Monitoring Board (DSMB) convened by NICHD will review data and safety information from 
study participants.
All AEs related to the study procedures or assessments (e.g., blood draws) and SUSARs 
related to study product will be reported. Safety ESIs will be recorded.
Guidelines for Assessing Association of an Adverse Event
A serious adverse event (SAE) or serious suspected adverse reaction or serious adverse 
reactions determined by the investigator or the sponsor is an AE or SAR that results in any of 
the following outcomes: 
•
Death 
•
Life-threatening AE (“life-threatening” means that the study participant was, in the 
opinion of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention) 
•
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
•
Inpatient hospitalization or prolongation of existing hospitalization 
•
Congenital abnormality or birth defect 
•
Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event. 


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Guidelines for Assessing Intensity of an Adverse Event
Safety events will be assessed by the study clinician using a protocol defined grading system.  
The investigator/delegate (defined as a clinician licensed to make a diagnosis) should use the 
following definitions when assessing intensity of an adverse event:
•
Mild - Participant is aware of symptoms or has minor findings but tolerates them well, 
and no or minimal intervention required  
•
Moderate - Participant experiences enough symptoms or findings to require intervention 
•
Severe - Participant experiences symptoms or findings that require significant 
intervention 
Guidelines for Assessing Causality
The investigator/delegate (defined as a clinician licensed to make a diagnosis) will use the 
following question when assessing causality of an AE to study intervention: Is there a 
reasonable possibility that the intervention caused the event? “Reasonable possibility” means 
that there is evidence to suggest a causal relationship between the study intervention and the 
AE. An affirmative answer designates the event as a suspected adverse reaction. 
The investigator/delegate (defined as a clinician licensed to make a diagnosis) must document 
his or her assessment of intensity, causality, and association in the participant records in a 
timely manner and submit safety reports as required by his or her IRB. 
Safety Events of Special Interest  
  
A safety event of special interest (SESI) is a select safety event that could be related to the 
study intervention. Safety ESIs will be solicited for their occurrence (No or Yes) and assessed 
by the investigator/delegate (defined as a clinician licensed to make a diagnosis) for intensity, 
causality, and association to provide uniform data collection of all events.
Safety ESIs are expected, pre-specified events, so they will not be reported in an expedited 
manner to the FDA but will be reviewed by the MM and the Data Safety Monitoring Board
(DSMB) convened by NICHD and reported to the FDA in the annual report.
The only SESI for this study will be the QTc interval obtained by ECG prior to study drug 
administration), 30 hours after study drug administration, and at the final study visit (96 hours 
post-administration). 
Collection Period and Reporting Procedures
Adverse Event information will be gained from direct monitoring of the study participants as well 
as from clinician observation and self-reporting by the study participants. The 
investigator/delegate (defined as a clinician licensed to make a diagnosis) must document his or 
her assessment of severity and causality in the participant records in a timely manner and 
submit safety reports as required by his or her IRB.
Death irrespective of causality, identified as either an unsolicited or solicited event (i.e., SESI), 
at any time through end of study will be reported.


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Serious Adverse Events/SUSARs will be collected for all participants, following the execution of 
informed consent through 7 days post last sample collection, and reported on the AE/SAE 
electronic case report form (eCRF).
Safety ESIs (Section 4.6.1 and 8.4.1) will be collected for all participants following the execution 
of informed consent through 7 days post last sample collection, and assessed for intensity, 
causality, and association, and reported in the data system. To determine if SESIs are dose 
related, additional data around solicited safety events will be recorded. 
Adverse Events will be recorded from the time of methadone administration until 96 hours (the 
final study visit) and reported in the data system.
Safety Event Follow-up and Sponsor Reporting
Adverse Events, SAEs, and SESIs directly related to study intervention/procedures will be 
followed until resolution, even if this period extends beyond the study-reporting period. 
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that resolution will remain chronic. If the event resolves during the 
study or follow-up period, a resolution date should be documented in the data system.
Adverse Events directly related to study intervention/procedures and SESIs (without a causal 
relationship to study intervention, that are not defined as an SAE) will be reported in the data 
system within 7 days of identification/site awareness. 
Adverse Events considered related to study intervention/procedures and all SAEs/SESIs
ongoing at the time of the last dose of study intervention will be followed for as long as 
necessary to adequately evaluate the participant’s safety or until the event stabilizes. If the 
event resolves during the study or follow-up period, a resolution date should be documented in 
the data system.
Serious Adverse Events, SUSARs, and SESIs that are associated with any of the criteria that 
define the event as an SAE will be reported in the data system within 24 hours of 
identification/site awareness. Upon entry in the Electronic Data Capture (EDC) system, these 
events will generate an automatic email notification to the MM and the sponsor. The 
investigator/delegate (defined as a clinician licensed to make a diagnosis) must document his or 
her assessment of intensity, causality, and association in the participant records in a timely 
manner and submit safety reports as required by his or her IRB.
The MM will review all safety events at the time they are reported. Any event that requires 
expedited reporting based on federal regulations (21 CFR 312.32) will be forwarded to the IND 
sponsor. The IND sponsor or its representative will submit expedited safety reports (e.g., IND 
safety reports) to the regulatory agencies, as necessary.  
Discontinuation of a Participant Due to Adverse Events
Any participant who experiences an AE may be withdrawn at any time from the study at the 
discretion of the investigator. The AE(s) should be reported in the EDC system, and the 
participant’s progress should be followed until the AE is resolved or considered stable. The MM
must be notified. If the AE may be related to overdose of study treatment, the package insert 
should be consulted for details of any specific actions to be taken.


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Pregnancy
Although not considered an AE, pregnancy must be reported on the specific pregnancy report 
form. If a participant is found to be pregnant during the study, the site must immediately report it. 
The site must document that they contacted the participant, advised the participant to obtain 
appropriate prenatal medical care, and referred the participant for such care. In addition, per the 
consent, researchers will follow the participant for the duration of the pregnancy and to obtain 
information (via direct examination or medical record review) to determine whether the resulting 
fetus/baby survived delivery or had any congenital abnormalities. If the fetus/newborn does not 
survive delivery or any congenital abnormalities are present, these must be reported as an SAE 
following the usual requirements for SAE reporting. Please note that if a pregnancy is reported, 
the participant’s subsequent weight, vital sign, and laboratory data will not be included in 
analyses for these variables. If the pregnancy is terminated early within the first 12 weeks of the 
pregnancy, inclusion of the participant’s subsequent weight/height, vital signs, and laboratory 
data in the analyses will be determined by the PTN study team.
Regulatory Reporting 
Any event that requires expedited reporting based on federal regulations will be forwarded to 
the IND sponsor via reporting on the study specific eCRF. The IND sponsor or its representative 
as detailed in the Transfer of Regulatory Obligations will submit expedited safety reports (e.g., 
IND safety reports) to the FDA and other regulatory agencies as necessary and will inform the 
investigators of such regulatory reports. Site investigators must submit safety reports as 
required by their IRB. Documentation of the submission and receipt by the IRB must be retained 
for each expedited safety report. 
Any event that requires reporting to Regulatory Authorities (e.g., SUSARS) based on applicable 
national regulations will be forwarded to the IND sponsor in time to meet reporting requirements.
Data and Safety Oversight (Medical Monitor/Data Safety Monitoring 
Board)
The study will be monitored by the BPCA Data Safety Monitoring Board (DSMB). The NIH 
charters the DSMB to support all research activities conducted under the BPCA PTN.
In addition, the study has designated a qualified and experienced physician not otherwise 
associated with this protocol to serve as the Medical Monitor (MM) and review all safety events
at the time they are reported and/or updated. The MM may request additional information 
regarding a site reported SAE; the Study PI is expected to provide requested information or 
materials to the MM in an expeditious manner to support the writing/submission of study safety 
reports. The MM will be available to study sites as needed. The study IND sponsor will also 
review all SAEs to determine regulatory reporting and will be available to sites as needed.
If safety concerns are identified, the MM may request a meeting of the DSMB to review safety 
data. The MM will also provide an initial report to the PTN PI/IND sponsor and an unbiased 
written report to the DSMB of the event per the DSMB charter/safety monitoring plan. At a 
minimum, the MM will comment on the outcomes of the safety event and the relationship of the 
safety event to the study product/intervention. The MM will also indicate whether they concur 
with the details of the report provided by the study site investigator. If no safety events prompt 
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The DSMB will convene and make recommendations on termination of the study based on 
review of safety reports and halting rules. The safety data will be compiled by the TDS. Based 
on the recommendations of the DSMB, PTN, and NIH/NICHD, the IND sponsor will decide to 
terminate or continue the study. 
Ad Hoc Meetings of the DSMB: The DSMB may convene an ad hoc meeting to discuss any 
issue of data and safety raised by the site investigator, MM, the IND sponsor, NICHD, or a 
member of the DSMB. At the discretion of the investigators, the IND sponsor, NICHD, and 
DSMB members, a non-serious safety event that is associated with the product or procedures 
may be considered as a trigger for an ad hoc DSMB meeting to assess the safety of the 
product/intervention, without resulting in halting the enrollment of the trial. 
 


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STUDY TERMINATION / HALTING
Study or Site Halting Criteria / Termination Criteria
This study may be terminated at any time by NICHD, the IND sponsor, or the DSMB. Reasons 
for termination include, but are not limited to, if in their judgment, no further benefits are to be 
achieved from the study or the intervention presents an unreasonable and significant risk to 
participants. If the study is terminated, notifications will be made to the regulatory authorities 
(e.g., FDA), investigators, IRBs, and study participants, in accordance with all applicable 
regulations governing the study and site/investigator.
Halting Rules
If any participant experiences a study drug-related SAE in the 24 hours following methadone 
administration, then study dosing administration will be stopped. The DSMB will be notified and 
will conduct a review, study activities will be allowed to proceed on previously enrolled and new 
participants. 
If 3 or more of participants enrolled to date experience a severe (Grade 3 or higher) reaction
related to the study drug, then the study will be halted for DSMB. 
Refer to Section 5.3 for requirements of participant safety follow-up following cessation of study 
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CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of study 
participants are protected, that the reported study data are attributable, legible, 
contemporaneous, original, accurate, and complete, and that the conduct of the study is in 
compliance with the currently approved protocol/amendment(s), with ICH GCP [E6(R2)], and 
with applicable regulatory requirement(s) including 21 CFR 312 Subpart D Responsibilities of 
Sponsors and Investigators. 
The Study PI, or as detailed in the Transfer of Regulatory Obligations, or his/her designee will 
conduct site-monitoring visits. Site visits will be made at standard intervals as defined by the 
clinical site monitoring plan and may be made more frequently as directed by the PTN 
Monitoring Team, IND sponsor and/or NICHD. Monitoring visits will include, but are not limited 
to, review of regulatory files, accountability records, data collection forms, informed consent 
forms, medical and laboratory reports, and protocol compliance. Study monitors will meet with 
investigators to discuss any problems and actions to be taken and document visit findings and 
discussions. 
The study-specific clinical site monitoring plan will supplement the BPCA project-wide clinical 
monitoring plan based on protocol risk assessments. 


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STATISTICAL CONSIDERATIONS
Pharmacokinetics (PK), Pharmacodynamics (PD), and safety analyses will be conducted. 
Participant demographics will be summarized. In addition, the number of participants enrolled, 
completed, discontinued early from study, and the reasons for discontinuation will also be 
summarized.
Descriptive statistics, such as the number of observations, mean, median, 95% confidence 
interval, standard deviation, standard error, minimum, and maximum, will be considered for 
continuous variables (such as age, weight, etc.). Other descriptive statistics, such as counts, 
proportions, and/or percentages, will be presented to summarize discrete variables (such as 
sex, race, etc.).
Study Endpoints 
Primary Endpoints
The list of primary endpoints includes the following: 
•
Clearance (CL) 
•
Volume of distribution (Vz)
•
Half-life (t1/2)
•
Area under the curve (AUC)
•
Maximum concentration (Cmax)
•
Time to maximum concentration (Tmax)
•
Minimum concentration (Cmin)
•
Elimination rate constant (ke)
Secondary Endpoints
The list of secondary endpoints includes the following:
•
Change in pupillometry
•
Observed sedation
•
Thermal pain tolerance thresholds
•
VAS from pre-dose to post-dose
•
Proportion of participants reporting AE, SAE, SUSAR from baseline to the end of safety 
follow-up
•
QTc from baseline to the end of safety follow-up
Exploratory Endpoints
The list of exploratory endpoints includes the correlation of plasma concentrations to VAS score 
at each post-dose VAS time point. Plasma concentrations are listed in the primary endpoints. 
Post-dose VAS time points are displayed in Table 5. 
Analysis Population
PK population: All enrolled participants who receive a dose of IV methadone and have at least
one evaluable PK sample will be eligible for the PK analysis population. 


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Safety population: All participants enrolled who received a dose of IV methadone will be 
included in the safety analysis. 
Efficacy (PK/PD) population: All participants enrolled who received at least one dose of IV
methadone and provided at least one PK sample and a corresponding efficacy assessment will 
be included in the efficacy analysis.
Analysis Plan
Noncompartmental analysis will be conducted to determine methadone PK. Compartmental 
modeling may be explored. Additional details are in the statistical analysis plan. 
Descriptive statistics, such as number of observations, mean, median, standard deviation, 
standard error, minimum, and maximum, will be presented for continuous variables (such as 
age, weight, etc.). Other descriptive statistics, such as counts, proportions, and/or percentages,
will be presented to summarize discrete variables (such as race, sex, etc.). All descriptive 
analyses will be presented overall. A 95% confidence level will be used for confidence intervals.
A detailed description of statistical methods and secondary analyses will be prepared and
presented in the statistical analysis plan prior to data lock for final analyses.
Primary Analysis
The dosing, sampling, and demographic information recorded on the eCRFs will be merged with 
bioanalytical information to create a PK dataset for methadone. A noncompartmental PK 
analysis will be performed in Phoenix WinNonlin (version 6.3 or later) using concentration–time 
data of methadone in plasma. The PK parameters for methadone will be summarized using 
descriptive statistics, including arithmetic mean, standard deviation, minimum, median, 
maximum, and geometric mean. 
Following the study dose on Day 0, peak drug concentration (Cmax), time at peak concentration 
(Tmax), and area under the concentration versus time curve (AUC) will be calculated using the 
observed data for methadone as appropriate and, if possible, depending on actual samples 
collected. AUC will be calculated using the linear trapezoidal method. At least 3 time points after 
the last dose with measurable plasma concentrations will be required for the calculation of 
AUC0-24. 
In addition, the following additional PK parameters will be estimated as appropriate and, if 
possible, depending on actual samples collected: apparent terminal elimination rate 
constant (ke), terminal-phase disposition half-life (t1/2), total clearance (CL, and volume of 
distribution during terminal phase (Vz). ke will be determined as the slope of a log-linear least 
squares of at least 3 concentration-time points after the last dose judged, by visual inspection, 
to be in the apparent terminal elimination phase. Half-life will be calculated as t1/2 = ln2/ke. 
Nominal sampling time will be used in PK calculations, unless actual times are needed. If 
samples are below the quantification limit and occur prior to the time at Cmax, a value of zero will 
be assigned; for samples occurring after Cmax, half the quantification limit will be assigned for a 
single below-quantifiable-limit sample, or zero for all values in consecutive samples that are 
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Compartmental methods will also be explored. Please see the PK analysis plan (PKAP) for 
additional details. 
Secondary Analysis
1) The relationship between methadone concentrations/other PK parameters and endpoints of 
change in pupillometry, observed sedation levels, thermal pain tolerance thresholds, change in 
VAS from pre to post dose, and change in respiratory rate will be evaluated using standard 
descriptive statistics. Descriptive summaries of the endpoints predose, postdose, end of follow-
up will be presented. The change between time points also will be presented, along with the 
95% CI, t-test, and p-value.
2) The following endpoints will be analyzed in the safety analyses:
Incidence of safety related events
A. AE related to study procedure
B. SAE related to study procedure
C. SUSAR related to study drug
D. Safety Events of Special Interest (QTc prolongation)
In addition, changes in QTc interval will be assessed over time.  
All AEs recorded during the study period will be coded with Medical Dictionary for Regulatory 
Activities (MedDRA) Version March 2018. Summaries of AE will be tabulated for the following 
types:
A. Number (%) of participants with any AE 
B. Number (%) of participants with any SAE 
C. Number (%) of participants withdrawn from treatment due to SUSAR
All summaries will be reported in total and by study site.  
Additional analyses (e.g., Exposure-Response [safety] analysis) and summaries may be derived 
if deemed appropriate and will be further described in the SAP.
Exploratory Analysis
A tabular or graphical data exploration of the relationship between safety endpoints (i.e., the 
occurrence of selected AEs) by methadone steady state exposures (e.g., AUC and Cmax) 
quantiles will be evaluated. The relationship between these steady-state exposures and the 
probability of experiencing AEs with possible covariates will be evaluated using logistic 
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Demographics and Baseline Characteristics
The number of participants who either completed or discontinued early from the study will be 
summarized. Demographic and baseline characteristics will be summarized.
Planned Interim Analyses 
No planned interim analyses will occur as part of this study.
Sample Size Considerations
For the primary objective, the sample size is based on the ability to precisely estimate the 
clearance in adults using population PK techniques. For IV methadone in healthy adult 
volunteers, we anticipate a CV% of 23 and 38% for R and S-enantiomers, respectively.15 Based 
on this range of CV%, 15 participants will be adequate to precisely describe CL with a 95% CI 
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FUTURE USE OF STUDY RECORDS AND BIOLOGICAL 
SPECIMENS  
The medical data and study information entered in the participant’s medical records will be kept 
per individual site policies for medical record retention. Other study records held at the study 
site will be kept until the FDA has completed any necessary review of the study results, or for a 
minimum of 2 years after the study has ended – whichever is longer. The research data 
collected in this study, and provided to the sponsor, will be kept indefinitely.  
Information about this study, including study results, will be published without further permission 
from the participant, as detailed in the ICF. Participants will not be identified in any publications 
or presentations made about the study.  
After the study is completed, information about the study, including de-identified study data, will 
be submitted to an NIH designated storage location, such as the NICHD Data and Specimen 
Hub or DASH (https://dash.nichd.nih.gov) or the NIH database of Genotypes and Phenotypes or 
dbGaP (https://www.ncbi.nlm.nih.gov/gap/). Controlled access means that only researchers who 
apply for and get permission to use the information for a specific research project will be able to 
access the information. 
With NIH approval, the data submitted to NIH-designated repositories may be used by other 
researchers for future research. The study data submitted to these NIH-designated repositories 
will be de-identified, meaning it will not include any information that can identify the participant. 
The study team may also share the de-identified study data with other researchers. When the 
participant’s de-identified study data are provided to other researchers for the purposes of future 
research, it will be done without obtaining additional permission from the participant.  
Biological specimens collected for study specific testing will be labeled at the site with a study-
provided barcode label. The specimen labels will only contain a unique code number; it will not 
include protected health information (PHI) or any other information that could identify the study 
participant. Specimens will be stored at the site and then shipped to an analytical laboratory for 
study-specific testing. After analysis, specimens will be stored until the FDA completes review of 
the final research study report and proposed drug label changes. Once FDA review of the study 
results is complete, and after consent for future use of these specimens is confirmed, the 
specimens will be submitted to an NIH storage facility.  
De-identified study specimens may be made available to other researchers for future research 
without obtaining additional permission from the participant. Although whole genome 
sequencing is not part of this study, study specimens containing genetic materials, may be 
made available to other researchers who may conduct whole genome sequence in the future.  
The participant’s study specimens will not be sold to anyone; however, the use of these 
specimens may result in commercial profit. There is no provision to provide the participant with 
financial compensation beyond what is described in the ICF. Biological specimens may be 
stored indefinitely. If a participant decides to withdraw permission to use his or her study data or 
specimens, he or she will be instructed per the ICF to contact the site investigator. Study data 
and samples including data collected using the participant’s specimen that has been recorded 
or collected prior to withdrawal will continue to be used, but no new data or specimens will be 
collected. 


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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 (R2), Section 4.9 and 21 CFR 312.62, and regulatory and institutional 
requirements for the protection of confidentiality of participants. Each site will permit authorized 
representatives of the sponsor, its designees, and appropriate regulatory agencies to examine 
(and, when required by applicable law, to copy) clinical records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety and progress. These 
representatives will be permitted access to all source data, which include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, participants’ memory 
aid or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and participant files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. Data collection forms will be derived from the eCRFs. 
 
 


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QUALITY CONTROL AND QUALITY ASSURANCE 
The Study PI will provide direct access to all trial-related sites, source data/documents, data 
collection forms, and reports for the purpose of monitoring and auditing by the sponsor and its 
designees, and inspection by local and regulatory authorities. The Study PI will ensure that all 
study personnel are appropriately trained and applicable documentation is maintained on site. 
The Study PI will verify that the clinical trial is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.  
The Study PI will implement quality control procedures, beginning with the data entry system, 
and generate data quality control checks that will be run on the data. Any missing data or data 
anomalies will be promptly clarified and resolved. 


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ETHICS/PROTECTION OF HUMAN PARTICIPANTS
Informed Consent Process
Informed consent is a process that is initiated prior to the participant agreeing to participate in 
the study and continuing throughout the individual’s study participation. 
Informed Consent of Adult Participants
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant, and written documentation of informed consent is required prior to starting 
study-specific procedures or intervention.
Documentation of Permission, Assent, and Consent
Consent must be documented using forms and processes determined by the Duke University 
Health System (DUHS) IRB.  
Prior to enrollment of participants into this trial, the protocol, the applicable informed consent
templates, and any materials or advertisements presented to participants will be reviewed and 
approved by the DUHS IRB and the site’s IRB of record. The consent templates approved by 
DUHS IRB and the site’s IRB of record will then be provided to sites and revised as necessary 
to comply with local regulations and institutional requirements. Sites are required to submit all 
changes to the templates to the study investigator or designee, which ensures compliance with 
U.S. and international regulations and sponsor (NIH) policies, prior to submission and approval 
to the IRB of record for each site. Notification of the IRB's approval, its composition, and the 
institution’s federal-wide assurance number will be provided to the Study PI or designee.
Should amendments to the protocol and consent documents be required, the amendments will 
be written by the sponsor, submitted by DEPRU, and approved by the DUHS IRB.
Participants may be compensated for their participation in this study. Compensation will be in 
accordance with the sponsor’s maximum compensation limits and institutional policies and 
procedures, must be documented in the consent form with the local IRB’s policies and 
procedures, requires IRB approval, and must be documented in the consent forms.
Upon reviewing the document, the investigator will explain the research study to the participant 
and answer any questions that may arise. The participant should have the opportunity to 
discuss the study and to think about it prior to agreeing to participate. Participants must be 
informed that participation is voluntary and that consent may be withdrawn from the study at any 
time, without prejudice. A copy of the executed informed consent document will be given to the 
participant for his or her records. 
Site staff may employ recruitment efforts approved by the IRB of record and per institutional 
policy prior to the participant consenting; however, before any protocol-specific procedures are 
performed to determine protocol eligibility, informed consent or waiver of informed consent must 
be obtained. The informed consent process will be conducted, and the form fully executed, i.e.,
signed and dated, before the participant undergoes any study-specific procedures. 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.


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The IND sponsor or designee will provide the investigator, in writing, with any new information 
that bears significantly on the participants' risk to receive the investigational product. This new 
information will be communicated by the site investigator to participants who consent to 
participate in the trial in accordance with IRB of record’s requirements. The informed consent 
document will be updated, and participants will be re-consented, if necessary.
Confidentiality and Privacy
This study is covered by a Certificate of Confidentiality (CoC) from the NIH. The CoC prevents 
U.S. courts and other U.S. agencies from forcing the study team to share information that may 
identify the participants during a legal or legislative action unless the participant allows this. The 
CoC does not keep the participants from sharing information about their participation in this 
study.
All research activities will be conducted in as private a setting as possible.
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their agents. This confidentiality is extended to cover testing 
of biological specimens in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
The Study PI will ensure that the use and disclosure of PHI obtained during a research study 
complies with the HIPAA Privacy Rule. Authorization is required from each research participant 
(i.e., specific permission granted by an individual to a covered entity for the use or disclosure of 
an individual’s PHI). A valid authorization must meet the implementation specifications under 
the HIPAA Privacy Rule. Authorization may be combined in the informed consent document (if 
approved by the IRB).
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
and regulatory agencies may inspect all documents and records required to be maintained by 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records.
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. Both the Study PI and the Institution at which the study is contracted to be 
conducted, will hold responsibility to maintain custody of all study records until the sponsor 
permits their destruction.
A unique study identification number will identify individual participants and their research data. 
The study data entry and study management systems used by clinical sites and by research 
staff will be secured and password protected. 
The clinical study site will permit access to all documents and records that may require 
inspection by the sponsor or its authorized representatives, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study.


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DATA HANDLING AND RECORD KEEPING
Data Handling
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. Data collection forms will be derived from the eCRFs for 
recording and maintaining data for each participant enrolled in the study. All source documents 
should be completed in a neat, legible manner to ensure accurate interpretation of data. 
Permanent ink is required to ensure clarity of reproduced copies. When making a change or 
correction, the original entry should be crossed out with a single line, and the change should be 
initialed and dated. Do not erase, overwrite, or use correction fluid or tape on the original. 
Data reported in the eCRF should be consistent with the data collection form/source documents, 
or the discrepancies should be documented. The sponsor and/or its designee will provide 
guidance to investigators on making corrections to the data collection forms and eCRFs.
Data Management Responsibilities
All data collection forms and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete. Adverse events must be 
assessed for intensity association and causality by a licensed clinician and reviewed by the 
Study PI or designee. Data collection is the responsibility of the clinical trial staff at the site 
under the supervision of the Study PI. During the study, the investigator must maintain 
complete, current, and accurate documentation for the study.
The Study PI will be responsible for data management, quality review, analysis, and reporting of 
the study data.
Data Capture Methods
Clinical data (including AEs) will be entered into a 21 CFR Part 11-compliant web-based data 
capture system. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the data collection forms/source 
documents.
Types of Data
Data for this study will include PK, PD, and safety data.
Timing/Reports
The DSMB convened by NICHD will make recommendations on study continuation based on 
the safety data collected according to DSMB charter.
The DSMB will convene and make recommendations on study continuation based on the safety 
data collected periodically.
Study Records Retention
Study records and source documents will be kept until the FDA has completed any necessary 
review of the study results, or for a minimum of 2 years after the study has ended – whichever is 
longer. The research data collected in this study will be kept indefinitely. 


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The disposition date related to FDA application will be posted on the PTN website for the 
Investigator’s reference. 
Protocol Deviations
A protocol deviation is any noncompliance/unplanned excursion from approved investigational 
plan (e.g., protocol, MOP), or ICH GCP guidelines. The noncompliance may be on the part of 
the participant, investigator, or site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
Each investigator must adhere to the investigational plan as detailed in the study protocol and/or 
associated study materials (e.g., MOPs, Forms Instructions, User Guides etc.). Each 
investigator will be responsible for the training of delegated staff and enrolling only those 
participants who have satisfied all protocol eligibility criteria.
All deviations will be recorded. The site is responsible for vigilantly identifying and reporting 
deviations within 5 working days of identification of the protocol deviation or within 5 working 
days of the scheduled protocol-required activity. All deviations must be promptly reported to the 
sponsor via the Electronic Data Capture system.
All deviations from the protocol must be reported in the study records/data system. Protocol 
deviations must be submitted to the local IRB per their guidelines. The Study PI and study staff 
are responsible for knowing and adhering to their IRB requirements.


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PUBLICATION POLICY 
Following completion of the study, the PTN PI may publish the results of this research in a 
scientific journal under the oversight/approval of the Publication Committee of the PTN. The 
PTN Publication Committee comprises representatives of the network cores, thought leaders, 
collaborators, and PTN and is responsible for generation and coordination of the publications 
that report scientific findings of the network. All public presentations (abstracts, manuscripts, 
slides and text of oral or other presentations, and text of any transmission through any 
electronic media) by participating investigators, participating institutions, and PTN that use PTN 
data and are intended to represent the PTN or are supported by the PTN will be reviewed by the 
PTN Publication Committee per the Publication Committee Charter.  
The PTN Publication Committee guarantees that the study results are presented by experts in 
the field that have working knowledge of the study design, implementation, data 
synthesis/analysis, and interpretation. The committee goals are to ensure that any confidential 
or proprietary information is protected, and that all appropriate statistical analyses have been 
included.  
The PTN Publication Committee will adhere to the trials registration policy adopted by the 
International Committee of Medical Journal Editors member journal. This policy 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. It is the responsibility of the IND sponsor to register this trial in an 
acceptable registry. 
The International Committee of Medical Journal Editors defines a clinical trial as any research 
project that prospectively assigns human participants to intervention or comparison groups to 
study the cause-and-effect relationship between a medical intervention and a health outcome. 
Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (e.g., 
phase 1 trials), would be exempt from this policy. 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central an electronic version of their final, peer-reviewed 
manuscripts upon acceptance for publication, to be made publicly available no later than 12 
months after the official date of publication. The NIH Public Access Policy ensures the public 
has access to the published results of NIH-funded research. It requires investigators to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. Further, the policy stipulates that these papers must be 
accessible to the public on PubMed Central no later than 12 months after publication.  
Refer to: 
http://publicaccess.nih.gov/  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html 


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ICF_000.pdf: 
 
Official Title:   
Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose 
Intravenous Methadone in Healthy Adult Volunteers (MTH02)   
 
NCT#:   
NCT05425420 
 
Informed consent document date:   
18Oct2023