A Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetic Profile of Multiple Ascending Doses of REL-1017 (d-Methadone) in Healthy Subjects
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Relmada Therapeutics, Inc.
- Enrollment
- 24
- Primary Endpoint
- Adverse Events (AEs)
Study Overview
Brief Summary
This study evaluated the safety, tolerance, and pharmacokinetics (PK) of d-methadone in a limited dose range, in multiple administrations in humans.
Detailed Description
This was a phase 1, single-center study carried out in healthy male and female subjects to investigate the safety, tolerability, and PK of multiple doses (25mg, 50mg, and 75mg once daily) of d-methadone for 10 days. It was a double-blind, randomized, placebo-controlled study in sequential cohorts of healthy subjects. Subjects participated in the study for approximately 7 weeks. Eligible subjects were randomized within 30 days of screening. Of the 8 subjects in each cohort, 2 subjects received placebo and 6 subjects received d-methadone. The duration of dosing ensured that steady-state plasma concentrations were achieved.
A single ascending dose study previously conducted by Relmada Therapeutics, Inc. demonstrated that the maximum tolerated single dose for oral d-methadone in healthy opiate-naive subjects was 150 mg. The single doses of d-methadone appeared to be safe, with no indication of respiratory depression or clinically significant QTc prolongation, and minimal subjective pharmacodynamic (PD) effects.
The following assessments and procedures ensured the safety of the subjects during the study:
- continuous cardiac telemetry for 8 hours post-dose to detect any potential cardiac issues
- continuous pulse oximetry monitoring for 8 hours post-dose to detect any potential respiratory distress
- presence of a safety catheter to administer rescue medication (naloxone), if needed
The following signs of opioid toxicity were deemed to be of special interest:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •healthy male or female subjects, 18 to 55 years of age, inclusive
- •body mass index (BMI) within the range of 18.0 to 30.0 kg/m2, inclusive, and a minimum weight of 50.0 kg
- •non-smoker for at least 3 months and tested negative on a breath carbon monoxide (CO) test
- •male subjects of reproductive potential must have been using and willing to continue using medically acceptable contraception from screening and for at least 2 months after the last study drug administration
- •female subjects of childbearing potential must have been using and willing to continue using medically acceptable contraception for at least 1 month prior to screening (at least 3 months for oral, transdermal, vaginal ring contraceptives) and for at least 2 months after last study drug administration
- •female subjects of non-childbearing potential must have met the criteria defined in the clinical protocol
- •able to speak, read, and understand English sufficiently to allow completion of all study assessments
- •must have understood and provided written informed consent, prior to the initiation of any protocol-specific procedures
Exclusion Criteria
- •self-reported substance or alcohol dependence (excluding nicotine and caffeine) within the past 2 years, and/or subjects who had ever been in a substance or alcohol rehabilitation program to treat their substance or alcohol dependence
- •subject-reported family history of substance abuse in an immediate family member (i.e., parent, sibling, or child)
- •history or presence of clinically significant abnormality as assessed by physical examination, medical history, 12-lead ECG, vital signs, or laboratory values, which in the opinion of the investigator would jeopardize the safety of the subject or the validity of the study results
- •chronic use of prescribed opioids (i.e., >120 days in a 6-month period) or any recreational use of opioids
- •evidence of clinically significant hepatic or renal impairment, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5× upper limit of normal (ULN) or bilirubin >1× ULN
- •history or family history of sudden unexplained death or long QT syndrome
- •QT interval corrected using Fridericia's formula (QTcF) >450 ms in females or >430 ms in males
- •history of hypotension
- •history or presence of any condition in which an opioid was contraindicated (e.g., significant respiratory depression, acute or severe bronchial asthma or hypercarbia, bronchitis, or had/was suspected of having paralytic ileus)
- •history of status asthmaticus, chronic pulmonary disease, or severe allergic reaction (including anaphylaxis) to any substance
- •use of an opioid within the 6 months prior to screening
- •use of a prohibited medication
- •positive urine drug screen
- •positive breath alcohol test; subjects with a positive result may have been rescheduled at the investigator's discretion
- •female subjects who were currently pregnant (had a positive pregnancy test)
- •history of allergy or hypersensitivity to methadone or related drugs (e.g., opioids)
- •positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
- •donation or loss of more than 500 mL of whole blood within 30 days prior to first drug administration
- •difficulty with venous access or unsuitable or unwilling to undergo catheter insertion
- •treatment with an investigational drug within 5 times the elimination half-life, if known (e.g., a marketed product) or within 30 days (if the elimination half-life is unknown) prior to first drug administration or was concurrently enrolled in any research judged not to be scientifically or medically compatible with this study
- •an employee of the sponsor or research site personnel directly affiliated with this study or their immediate family member, defined as a spouse, parent, sibling, or child, whether biological or legally adopted
- •a subject who, in the opinion of the investigator or designee, was considered unsuitable or unlikely to comply with the study protocol for any reason
Arms & Interventions
Arm 1
100 mL Ocean Spray® Diet Cranberry Juice
Intervention: Placebo (Drug)
Arm 2
REL-1017 25 mg in 100 mL of Ocean Spray® Diet Cranberry Juice
Intervention: REL-1017 (Drug)
Arm 3
REL-1017 50 mg in 100 mL of Ocean Spray® Diet Cranberry Juice
Intervention: REL-1017 (Drug)
Arm 4
REL-1017 75 mg in 100 mL of Ocean Spray® Diet Cranberry Juice
Intervention: REL-1017 (Drug)
Outcomes
Primary Outcomes
Adverse Events (AEs)
Time Frame: Change from pre-dose, Days 1 through 13, and Days 14, 16±1, and 18±1
Spontaneously reported and observed AEs were recorded throughout the study, and AEs were elicited using a non-leading question at designated time points. Regardless of seriousness, intensity, or presumed relationship to study drug, all AEs were recorded in the source documentation from the time of first contact with the subject (e.g., screening) until the end of the follow-up period of the study. AEs that occurred after medical screening and prior to administration of the first dose of study drug were recorded in the source documentation as baseline signs and symptoms.
Secondary Outcomes
- Plasma levels(Days 1 through 13, and Days 14, 16±1, and 18±1)