Efficacy and Safety Evaluation of Dextromethadone Hydrochloride as Adjunctive Therapy in Major Depressive Disorder with Inadequate Response to Antidepressants
- Trial ID
- 2023-507399-27-00
- Protocol
- REL-1017-305
- Sponsor
- Mggm LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **therapeutic efficacy** of REL-1017 compared to placebo in participants with an inadequate response to ongoing antidepressant therapy (ADT) at Day 28, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS10) total score. This is clinically relevant as it aims to address the unmet need for effective adjunctive treatments in patients with Major Depression who do not respond adequately to standard ADT.
Secondary objectives include:
- Evaluating the therapeutic efficacy of REL-1017 compared to placebo in terms of the decrease from baseline to Day 7 of the MADRS10 total score.
- Assessing the MADRS10 response rate, defined as an improvement of ≥50% compared with the total baseline score, at Day 28.
- Determining the MADRS10 remission rate, defined as a total score ≤10, at Day 28.
- Measuring the decrease from baseline to Day 28 of the Clinical Global Impression of Severity (CGI-S) score.
- Evaluating the safety and tolerability of REL-1017.
- Assessing the effect of REL-1017 on electrocardiographic parameters.
- Evaluating the impact of REL-1017 for 28 days compared to placebo on measures of depression, anxiety, sleep, sexual function, cognitive function, select biomarkers, and quality of life in subjects with inadequate response to ongoing ADT.
- Investigating the effect of REL-1017 on potential blood markers of Major Depressive Disorder (MDD) or treatment outcome.
- Evaluating the pharmacokinetics (PK) of REL-1017.
Participants
The clinical trial involves a total of **16 participants** diagnosed with **Major Depression**. The study population includes both male and female subjects, aged between 18 to 65 years, with a **body mass index (BMI)** ranging from 18.5 to 30.0 kg/m². Participants were selected based on their inadequate response to ongoing antidepressant therapy (ADT) and a confirmed diagnosis of moderate to severe major depressive disorder (MDD) as per the Diagnostic and Statistical Manual, Fifth Edition (DSM-5). The trial does not include a vulnerable population. Participants are required to maintain a stable dosing regimen of their current ADT throughout the study. The selection criteria ensure that participants have a current major depressive episode (MDE) lasting from 8 weeks to 24 months, with a baseline Montgomery-Åsberg Depression Rating Scale (MADRS10) score not exceeding >30% and <20% compared to the screening MADRS. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants must be willing to adhere to study requirements and use effective contraception if applicable.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of **dextromethadone hydrochloride** (REL-1017) as an adjunctive treatment for individuals with **major depression** who have shown an inadequate response to ongoing antidepressant therapy (ADT). This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study. The trial will span approximately two years, with an estimated recruitment start date of November 1, 2024, and an estimated end date of December 31, 2026.
Participants will be randomly assigned to receive either REL-1017 or a placebo, administered orally in tablet form. The maximum daily dose of REL-1017 is 75 mg, with a total treatment period of 28 days. The primary endpoint is the decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS10) total score from baseline to Day 28, comparing REL-1017 to placebo. Secondary endpoints include changes in MADRS10 scores at various time points, response and remission rates, and other clinical assessments.
The study will include several visits: an initial screening visit to confirm eligibility, a baseline visit on Day 1, and follow-up visits on Days 7, 14, and 28. The end-of-study visit will occur on Day 28, where final assessments will be conducted. Participants are expected to be involved in the study for approximately 28 days, with conditions for early termination including non-compliance with study requirements, adverse events, or withdrawal of consent.
Inclusion criteria require participants to be aged 18 to 65 years, with a body mass index (BMI) between 18.5 and 30.0 kg/m². They must have a confirmed diagnosis of moderate to severe major depressive disorder (MDD) as per the DSM-5, with a current major depressive episode (MDE) lasting 8 weeks to 24 months. Participants must have been on a stable ADT regimen for at least 6 weeks prior to screening and demonstrate a 10% to 50% improvement in symptoms. Exclusion criteria are not specified in the provided data.
Treatment
The clinical trial involves the administration of **dextromethadone hydrochloride**, an experimental medication identified by the sponsor product code REL-1017. This medication is formulated as a **tablet** and is intended for **oral use**. The maximum daily dose is 75 mg, with a total maximum dose of 750 mg over a treatment period of 28 days. The active substance, dextromethadone hydrochloride, is of chemical origin. The trial aims to evaluate the efficacy of REL-1017 as an adjunctive treatment for Major Depressive Disorder in participants with an inadequate response to ongoing antidepressant therapy. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.
The study also includes a **placebo** group, which receives identical tablets containing inactive ingredients such as Lactose Monohydrate Fast-F lo, Cellulose Microcrystalline PH-102, Croscarmellose Sodium, Colloidal Silicon Dioxide-Cabot, and Magnesium Stearate 5712. These placebo tablets are designed to match the experimental medication in appearance and administration route, ensuring the double-blind nature of the trial. The placebo serves as a comparator to assess the therapeutic efficacy of REL-1017. Participants' adherence to the placebo regimen will be similarly monitored to maintain the integrity of the study's findings.
Efficacy
The efficacy of REL-1017 as an adjunctive treatment for Major Depressive Disorder (MDD) will be assessed in a Phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS10) total score from Baseline to Day 28 in participants with an inadequate response to ongoing antidepressant therapy (ADT). Secondary endpoints include the decrease in MADRS10 total score from Baseline to Day 7, MADRS10 response rate (defined as an improvement of ≥50% compared to the total Baseline score) at Day 28, and MADRS10 remission rate (total score ≤10) at Day 28. Additional secondary endpoints involve changes in the Clinical Global Impressions-Severity (CGI-S) score, CGI-Improvement (CGI-I) score, and various other scales and measures such as the Digit Symbol Substitution Test (DSST), Arizona Sexual Experience Scale (ASEX), Sheehan Disability Scale (SDS), and Hamilton Anxiety Depression Scale (HAM-A).
Efficacy assessments will be conducted using validated scales and instruments at specified timepoints, including Baseline, Day 7, and Day 28. The trial will also evaluate the effect of covariates such as baseline severity of depression, tachyphylaxis/tolerance, treatment-resistant depression (TRD), time since first diagnosis of MDD, sex, and age on the primary endpoint. Safety and tolerability will be monitored through treatment-emergent adverse events (TEAEs), vital signs, physical examinations, clinical laboratory parameters, and the Columbia Suicide Severity Rating Scale (C-SSRS). The trial is designed to provide comprehensive data on the efficacy and safety of REL-1017 in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent.
- Male or female participant, aged 18 to 65 years, inclusive.
- Body mass index (BMI) between 18.5 and 30.0 kg/m2, at Screening
- 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
- Women of childbearing potential (WOCBP) and men whose sexual partners are WOCBP must use at least 1 highly effective method of contraception from Screening and for at least 2 months after the last study drug administration
- Diagnosed with MDD as defined by the Diagnostic and Statistical Manual, Fifth Edition (DSM-5), and confirmed by the SCID-5 CV.
- Diagnosed with a current MDE lasting from 8 weeks to 24 months as defined by the DSM-5 and confirmed by the SCID-5 CV, as well as confirmation of MADRS10 and PHQ9 scores of moderate to severe MDD and contextual appropriateness to be a participant in this study by the Investigator.
- Diagnosed with a current MDE lasting from 8 weeks to 24 months as defined by the DSM-5 and confirmed by the SCID-5 MDD, as well as confirmation of MADRS10 score, ATRQ, and contextual appropriateness to be a participant in this study by the Investigator
- Treated for at least 6 weeks prior to Screening, stabilized for at least 6 weeks prior to Baseline, and experiencing approximately 10% to 50% improvement, as assessed by the clinician, and documented on the ATRQ, from an approved dosing regimen of ADT (eg, SSRI, SNRI, bupropion [a NDRI and nicotinic receptor antagonist] or atypical antipsychotic adjunctive antidepressant, alone or in combination) during the current MDE, and committed to remaining on the same stable dosing regimen for the Screening period and for the entire study, at or above the minimally adequate dose listed in the ATRQ. Subjects with clinician assessed antidepressant tolerance/tachyphylaxis are eligible even if the current ADT response is <10%.
- As ascertained by an independent adjudicator, the data transcribed in the eCRF from the ATRQ, SCID-5-CV, PHQ9, MADRS, C-SSRS, HAM-A are complete, consistent and compatible with the primary diagnosis of moderate to severe MDD with inadequate response to an adequate trial of antidepressants as defined in the criterion above. • A cut-off of ≥ 26 on MADRS is defined for study entry. The remaining scales will be checked by the independent adjudicator only for ensuring consistency of diagnosis for inclusion of patients, i.e. diagnosis of MDD as defined by the DSM-5.
- Baseline (Day 1) MADRS10 score not exceeding >30% and <20% compared to the Screening MADRS
Exclusion Criteria
- 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.
- 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
- Triplicate 12-lead ECG with average QTcF ≥450 msec, and/or a QRS interval ≥120 msec at Screening
- 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%)
- Any long-term use (ie, >120 days in a 6-month period) of prescribed opioids or controlled substances within 6 months, prior to Screening – as verified by appropriate medical records.
- More than 3 doses of opioids use within 30 days prior to Baseline
- Pro Re Nata (PRN) use of any anxiolytic, antipsychotic, anticonvulsant/antiepileptic, mood stabilizer, or stimulant medications or supplements within 30 days prior to Screening. Note: Participants should be medically stable; when discontinuation of a prohibited medication is indicated, the prohibited medication should be appropriately tapered to avoid withdrawal symptoms. Benzodiazepines, atypical antipsychotic drugs, anticonvulsants/antiepileptic drugs, mood stabilizers, stimulants, and supplements, including St. John’s Wort, [Hypericum Perforatum), taken regularly and daily at a stable dose for at least six weeks prior to Screening, for the treatment of MDD or its symptoms, are permitted.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Nov 2024 | 130 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
identical tablets containing Lactose Monohydrate Fast-F lo, Cellulose Microcrystalline PH-102, Croscarmellose Sodium, Colloidal Silicon Dioxide-Cabot, and Magnesium Stearate 5712. | Placebo | N/A | — | — | — | N/A |