MethaLoad Dose-Finding Study

A Dose-Finding Study of Methadone Loading Dose Initiation for Opioid Use Disorder With Fentanyl Use

The goal of this study is to develop a loading dose approach to starting methadone to treat opioid use disorder with fentanyl use ("fentanyl OUD", herein). This study is a participant- and assessor- blinded dose-finding study using the Bayesian optimal interval (BOIN) design. Investigators aim to recruit n=24 participants with fentanyl OUD to a research unit for monitored methadone initiation. Participants will be randomized to standard initiation vs. loading dose initiation at one of four doses.

Study Overview

• Status: Recruiting
• Conditions: Opioid Use Disorder (OUD)
• Intervention / Treatment: Drug: Methadone hydrochloride

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ashish P Thakrar, MD, MS; Phone Number: (215) 662-2250; Email: apthakrar@pennmedicine.upenn.edu
• Study Contact Backup: Name: Kyle Kampman, MD; Email: kampman@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Penn Center for Studies of Addiction (CSA)
      • Contact: Megan Ivey; Phone Number: 215-746-0222; Email: Megan.Ivey@pennmedicine.upenn.edu
      • Principal Investigator: Ashish P Thakrar, MD, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Male, female, transgender, or non-binary, aged 18 years or older
2. DSM-5 criteria for opioid use disorder, moderate-severe
3. Fentanyl positive urine drug test
4. Able to provide a dated & written informed consent in English prior to the conduct of any study related procedures
5. Stated willingness to comply with all study procedures and availability for the duration of the study
6. Ability to take oral medication and be willing to adhere to the dosage regimen
7. Interest in starting methadone treatment for opioid use disorder at one of three locations: Merakey Parkside at 5000 Parkside, Merakey 5429 Germantown Avenue, or Merakey 1745 North 4th Street
8. Reliable access to a working phone

Exclusion criteria:

1. Hypersensitivity or allergy to methadone that is previously documented
2. Pregnancy or actively lactating (with urine pregnancy test performed on screening and repeated on admission to the unit prior to randomization)
3. Taking medications for opioid use disorder, per self-report or per urine drug testing detection of buprenorphine or methadone
4. At risk of benzodiazepine or alcohol withdrawal as defined by: prior benzodiazepine or alcohol withdrawal in the past 3 months, current daily use of benzodiazepines or alcohol, or DSM-5 criteria for hypnotic-sedative or alcohol use disorder
5. At risk of severe medetomidine withdrawal based on: serum or urine testing for medetomidine (if available), prior withdrawal syndrome requiring intensive care unit admission within past 6 months, and/or severe nausea/vomiting during first 4 hours of withdrawal, at the discretion of the study physicians
6. At risk for methadone-induced QT-prolongation: prolonged QTc on screening or admission EKG (greater than 450ms in men, greater than 460ms in women), history of QT prolongation, previously documented long QT syndrome, history of ventricular arrhythmia (e.g., torsades de pointes), history of cardiac hypertrophy, history of cardiac conduction abnormalities, taking medications that affect cardiac conduction (at study physician discretion; including but not limited to: amiodarone, flecainide, sotalol, azithromycin, ciprofloxacin, levofloxacin, citalopram, escitalopram, hydroxychloroquine, chlorpromazine, haloperidol, donepezil, ibogaine, cilostazol), serum potassium concentration less than 3.5 mg/dL, or serum magnesium concentration less than 1.7 mg/dL.
7. Significant hepatic dysfunction, defined as: AST and/or ALT 3x upper limit of normal, or total bilirubin 1.5x upper limit of normal
8. Significant renal dysfunction, defined as: eGFR less than or equal to 60 mL/min
9. Chronic hypotension (<90/50 mmHg) or episodic symptomatic hypotension, defined as a history of active or recurrent orthostatic hypotension or syncope
10. Significant pulmonary disease, defined as: baseline SpO2 <95% on screening or admission, requiring oxygen at home (chronically or at bedtime), or COPD with modified MRC Dyspnea Scale greater than 2 ("I stop for breath after walking about one city block")
11. Suspected gastrointestinal obstruction, per medical history
12. Active, chronic use of the CYP3A4-inducers or -inhibitors rifampin, phenytoin, St John's wort, phenobarbital, carbamazepine, voriconazole, efavirenz, nelfinavir, nevirapine, ritonavir, and lopinavir/ritonavir, abacavir, or amprenavir
13. Pending legal action that could prohibit participation and/or compliance in study procedures
14. Presence of any other psychiatric and/or medical disorder that, in the opinion of the PI, will interfere with completion of the study or place the patient at heightened risk through participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment as usual (TAU); Day 1: 40mg oral methadone Day 2: 40mg oral methadone	Drug: Methadone hydrochloride; Methadone loading dose initiation (vs. standard initiation in the TAU arm)
Experimental: Loading Dose; Day 1: loading dose (60mg, 80mg, 100mg, or 120mg oral methadone) Day 2: 50% of the loading dose (30mg, 40mg, 50, or 60mg oral methadone)	Drug: Methadone hydrochloride; Methadone loading dose initiation (vs. standard initiation in the TAU arm)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity (DLT) rate	The primary objective of the study is to identify a methadone loading dose approach appropriate for future study as an alternative initiation strategy for individuals with OUD using fentanyl or other high-potency synthetic opioids. The loading dose appropriate for future study will be identified as the highest loading dose with a dose-limiting toxicity (DLT) rate less than 10%. DLT definition: the proportion of individuals in each loading dose arm who meet any one of four safety outcomes within 24 hours of methadone loading dose administration: (1) Richmond Agitation-Sedation Scale (RASS) less than -1, (2) respiratory rate (RR) less than 8 breaths per minute, (3) peripheral oxygen saturation (SpO2) less than 92%, or (4) corrected QT interval (QTc) greater than 500ms.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid withdrawal severity	Peak and time-weighted mean subjective opioid withdrawal (using the Subjective Opioid Withdrawal Scale, SOWS) and the Clinical Opiate Withdrawal Scale (COWS) over 24 hours after initial methadone dose	24 hours
Opioid craving	Peak and time-weighted mean opioid craving, using a visual analogue scale (VAS) assessment (1-100) over 24 hours after initial methadone dose	24 hours after initial methadone dose
Peak plasma methadone concentration	Peak plasma methadone concentration after initial loading dose (Day 1) and after first maintenance dose (Day 2)	48 hours

Collaborators and Investigators

• Sponsor: University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2025
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: March 10, 2025
• First Submitted That Met QC Criteria: March 10, 2025
• First Posted (Actual): March 14, 2025

Study Record Updates

• Last Update Posted (Estimated): October 14, 2025
• Last Update Submitted That Met QC Criteria: October 9, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: fentanyl; opioid use disorder; methadone; opioid addiction; OUD; opiate addiction
• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Opioid-Related Disorders; Organic Chemicals; Ketones; Methadone
• Other Study ID Numbers: 857972

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No