MethaLoad Dose-Finding Study

Phase 1

Not yet recruiting

• Conditions: Opioid Use Disorder (OUD)
• Interventions: Drug: Methadone hydrochloride

• Registration Number: NCT06877858
• Lead Sponsor: University of Pennsylvania

Brief Summary

The goal of this proposal is to develop a "loading dose" approach to starting methadone to treat fentanyl opioid use disorder (OUD). We aim to conduct an assessor-blinded dose-finding study of 24 participants with fentanyl OUD recruited to a research unit for monitored methadone dosing. Participants will be randomized to standard methadone initiation vs. one of three loading dose approaches. The primary goal is to identify the maximum tolerated methadone loading dose appropriate for future study.

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-10
• Study First Submitted QC: 2025-03-10
• Last Update Submitted: 2025-03-10
• Study First Posted: 2025-03-14
• Last Update Posted: 2025-03-14
• Study Start: 2025-09-01
• Primary Completion: 2027-03
• Study Completion: 2027-07

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. Able to provide a dated written informed consent in English prior to the conduct of any study related procedures
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male, female, transgender, or non-binary aged 18 or older
4. In good general health as evidenced by medical history.
5. Fentanyl positive urine drug test
6. Ability to take oral medication and be willing to adhere to the dosage regimen
7. For females of reproductive potential: negative urine pregnancy test on screening and on admission
8. DSM-5 criteria for opioid use disorder, moderate to severe
9. Interest in starting methadone treatment for opioid use disorder at Merakey Parkside (our partner outpatient treatment program where we will send patients on discharge from the study)

Exclusion Criteria

1. Previously documented hypersensitivity or allergy to methadone
2. Prolonged QTc (=450ms in men, =460ms in women), previously documented long QT syndrome, history of QT prolongation, or history of ventricular arrhythmia (e.g., torsades de pointes)
3. Pregnancy or lactation
4. DSM-5 criteria for benzodiazepine or alcohol use disorder
5. Urine drug testing at screening positive for buprenorphine and/or methadone
6. AST and/or ALT 3x upper limit of normal or total bilirubin or equal to 1.5x upper limit of normal
7. eGFR less than or equal to 60 mL/min
8. Chronic hypotension (<90/50 mmHg) or episodic symptomatic hypotension (history of active or recurrent orthostatic hypotension or syncope).
9. Significant chronic pulmonary disease: COPD with modified MRC Dyspnea Scale >=3 ("I stop for breath after walking about one city block") or requiring oxygen (chronically or at bedtime)
10. 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
11. Significant medical symptoms, psychiatric symptoms, or dementia that, in the opinion of the investigators, would preclude compliance with the protocol, cooperation in the study, obtaining informed consent, or ability to safely participant in the study
12. Pending legal action that could prohibit participation and/or compliance in study procedures

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment as usual (TAU)	Methadone hydrochloride	Day 1: 30mg oral methadone, followed by 10mg 4 hours later for COWS \>=6 Day 2: 40mg oral methadone, followed by 10mg 4 hours later if COWS \>=6
Loading dose	Methadone hydrochloride	Participants will receive a loading dose on Day 1 followed by 50% of that loading dose on Day 2. We will assess safety of three loading doses: 60mg, 80mg, and 100mg. The first 3 participants randomized to the Loading Dose arm will receive 60mg loading dose (60mg Day 1 followed by 30mg Day 2). Subsequent cohorts of 3 participants randomized to the Loading Dose arm will receive 60mg, 80mg, or 100mg loading doses on Day 1 (followed by 50% of the loading dose on Day 2) based on the observed dose-limiting toxicity rate as described in the Bayesian Optimal INterval (BOIN) Design for dose-finding studies. Day 1: loading dose (60mg, 80mg, or 100mg oral methadone) Day 2: 50% of the loading dose (30mg, 40mg, or 100mg oral methadone), followed by 10mg 4 hours later if COWS \>=6

Primary Outcome Measures

Name	Time	Method
Dose-limiting toxicity rate	24 hours	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 \<15%. DLT definition: the proportion of individuals in each loading dose arm who meet at least one of three safety outcomes: (1) Richmond Agitation-Sedation Scale less than -2, (2) respiratory rate less than 8 breaths per minute, or (3) corrected QT interval greater than 500ms on ECG.