A Study to Evaluate the Efficacy and Safety of REL-1017 As Adjunctive Treatment of Major Depressive Disorder (MDD)

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 As Adjunctive Treatment for Major Depressive Disorder (MDD)

Study Overview This clinical trial is a Phase 3 research study designed to test the safety and effectiveness of an investigational drug called REL-1017 (esmethadone HCl). The goal is to determine if REL-1017 can help people with major depressive disorder (MDD) who are already taking other antidepressant medications but have not experienced enough improvement.

Why This Study Is Important MDD is a serious condition that affects mood, cognition, motivation, energy, and daily life. Some people do not respond fully to standard antidepressants. REL-1017 is being tested as an additional treatment to see if it can improve symptoms more effectively.

Who Can Participate The study is enrolling adults diagnosed with major depressive disorder who do not have enough relief from their current antidepressant medications. Specific criteria must be met to join the study.

What Happens in the Study Participants will be randomly assigned to receive either REL-1017 or a placebo (an inactive substance) along with their current antidepressant. This process helps researchers understand the effects of the drug. Neither the participants nor the researchers will know who receives REL-1017 or the placebo during the study.

Study Details Duration: The study involves several weeks of treatment and follow-up visits. Assessments: Participants will complete health evaluations, including physical exams and questionnaires, to monitor progress and side effects.

Costs: Study-related treatments and assessments are provided at no cost to participants.

Potential Benefits and Risks Benefits: Participants may experience improvements in depressive symptoms. Risks: As with any investigational medication, there may be side effects. All participants will be closely monitored by the study team.

Study Overview

• Status: Withdrawn
• Conditions: Major Depressive Disorder (MDD)
• Intervention / Treatment: Drug: Placebo; Drug: REL1017 (esmethadone HCI) (active drug)

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20123
    • Mediolanum Cardio Research
• Switzerland
  • Lugano, Switzerland, 6900
    • Clinical Trial Unit - Ente Ospedaliero Cantonale (CTU-EOC) Area Formazione medica e Ricerca (AFRi)

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Written informed consent.
2. Male or female participant, aged 18 to 65 years, inclusive, at Screening.
3. Body mass index (BMI) between 18.5 and 30.0 kg/m2, inclusive, at Screening.
4. Participant understands the study requirements, is willing and able to commit to meet all study requirements, adhere to both approved ADT and study drug regimen, and complete all assessments and all scheduled visits, per Investigator judgment.

Exclusion Criteria:

1. 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 participant or the validity of the study results, including established QT prolongation, long QT syndrome, torsades de pointes, bradyarrhythmia, ventricular tachycardia, uncompensated heart failure (greater than NYHA Class 1 CHF), uncontrolled hypokalemia, or uncontrolled hypomagnesemia.
2. Any medical, psychiatric condition, or social context that, in the opinion of the Investigator, is likely to unfavourably alter the risk-benefit of participant, to interfere with protocol compliance, or to confound safety or efficacy assessments.
3. Triplicate 12-lead ECG with average QTcF ≥450 msec, and/or a QRS interval ≥120 msec at Screening.
4. Poorly controlled diabetes as defined by a glycosylated hemoglobin (HbA1c) >8.5% (69 mmol/mol), despite standard care. (Note: re-screening of patients who has failed the screening process due to not meeting this exclusion criterion is allowed after diabetes treatment adjustment and level of glycosylated hemoglobin (HbA1c) back to <8.5%)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; The placebo serves as a control to evaluate the effectiveness and safety of REL-1017. It is an inactive substance that matches the active drug in appearance but contains no active ingredients. The placebo group allows researchers to compare outcomes, such as changes in depressive symptoms, with the active drug group. The double-blind design ensures neither participants nor researchers know who is receiving the active treatment or placebo, eliminating bias. The placebo also helps assess whether observed side effects are due to the drug or unrelated factors. Participants are randomly assigned to receive either REL-1017 or the placebo, both administered once daily for 28 days. This helps establish REL-1017's clinical effectiveness and safety in treating Major Depressive Disorder (MDD).
Experimental: REL 1017-305	Drug: REL1017 (esmethadone HCI) (active drug); REL-1017 is an investigational drug administered as an oral tablet, once daily. The dosing regimen includes a 75 mg dose on Day 1 (three tablets) in the clinic, followed by 25 mg daily (one tablet) at home from Day 2 to Day 28, with regular safety, efficacy, and tolerability assessments REL-1017 (esmethadone HCl) is under investigation as a novel NMDAR antagonist. Unlike racemic methadone, it lacks opioid-like effects such as dependency or respiratory depression. REL-1017 also lacks dissociative effects seen with more potent NMDAR antagonists such as ketamine. Finally, REL-1017 does not appear to have metabolic or neurological side effects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MADRS10	To evaluate the therapeutic efficacy of REL-1017 compared to placebo in participants with inadequate response to ongoing ADT at Day 28 on the Montgomery-Åsberg Depression Rating Scale (MADRS10) total score. Scale: Montgomery-Åsberg Depression Rating Scale (MADRS) Minimum and Maximum Values: The scale ranges from 0 to 60. Interpretation of Higher Scores: Higher scores indicate greater severity of depression. Specific Ranges: 0-6: Normal/no symptoms. 7-19: Mild depression. 20-34: Moderate depression. 35-60: Severe depression.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MADRS10	Decrease from Baseline to Day 7 of the MADRS10 total score Scale: Montgomery-Åsberg Depression Rating Scale (MADRS)	7 days
MADRS10	MADRS10 response rate (improvement ≥50% compared with total Baseline score) at Day 28 Scale: Montgomery-Åsberg Depression Rating Scale (MADRS)	28 days
MADRS10	MADRS10 remission rate (total score ≤10) at Day 28 Scale: Montgomery-Åsberg Depression Rating Scale (MADRS)	28 days
CGI-S	Decrease from Baseline to Day 28 of the CGI-S score Scale: CGI-S The CGI-S measures the severity of the disease using a 7-point Likert scale ranging from 1=normal, not at all ill to 7=among the most extremely ill participants	28 days

Collaborators and Investigators

• Sponsor: MGGM LLC

Study record dates

Study Major Dates

• Study Start (Estimated): December 27, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: December 13, 2024
• First Submitted That Met QC Criteria: December 13, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 3, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: MDD; Adjunctive therapy; NMDA; REL-1017; Esmethadone
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: REL-1017-305

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: Yes