Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD

NCT03051256 | Completed Phase 2 Results FDA Drug

• 1 other identifier: REL-1017-202
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 10

Brief Summary

This a Phase 2a, multicenter, randomized, double-blind, placebo controlled 3 arm study to assess the safety and tolerability of multiple oral doses of REL-1017 25 mg and 50 mg as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD). The patients will be adults with MDD who are diagnosed with a current MDE who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication. This population will provide the opportunity to compare the safety and efficacy effects of treatment with an approved antidepressant in conjunction with REL-1017 versus the effects of an antidepressant alone. This study includes in-patient and out-patient periods.

Conditions

Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant

Keywords

REL-1017; d-Methadone; Methadone; Depression; Refractory Depression; Antidepressant; Adjunctive Treatment; NMDA Receptor Antagonist; Excitatory Amino Acid Antagonist; Glutamate Antagonist

Outcome Measures

Primary Outcomes (1)

• Incidence of Treatment Emergent Adverse Events (AEs) [Safety and Tolerability]

  Spontaneously reported or observed AEs will be recorded and reported throughout the study, and AEs will be elicited using a non-leading question at every visit from Screening through the Day 21 assessment. An AE was any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and may not necessarily have a causal relationship with the administered treatment. An AE could therefore be any unfavorable and unintended sign (including a clinically significant laboratory abnormality, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, regardless of relationship to the medicinal (investigational) product. During the study, an AE could also occur outside the time that the investigational product(s) was given (e.g., during the time from discontinuation of prohibited medications).

  21 days

Secondary Outcomes (15)

• ECG Parameters [Safety]

  Screening, Day -1, Day 1 hour 2, 8, Day 2 hour 2, 8, Day 3-7 hour 2, Day 8, Day 9, and Day 14

• Columbia Suicide Severity Rating Scale (C-SSRS) [Safety and Tolerability]

  Day -1, Day 1, Day 2, Day 8, Day 9 and Day 14

• Montgomery-Asberg Depression Scale (MADRS)

  Change from Baseline to Day 7

• Montgomery-Asberg Depression Scale (MADRS)

  Change from Baseline to Day 14

• Symptoms of Depression Questionnaire (SDQ)

  Change from Baseline to Day 7

Study Arms (3)

REL-1017 25 mg

EXPERIMENTAL

REL-1017 75 mg of powder in 100 mL of Ocean Spray® Diet Cranberry Juice daily on Day 1, 25 mg of powder in 100 mL Ocean Spray® Diet Cranberry Juice daily on Day 2-7.

Drug: REL-1017

REL-1017 50 mg

EXPERIMENTAL

REL-1017 100 mg of powder in 100 mL of Ocean Spray® Diet Cranberry Juice daily on Day 1, 50 mg of powder in 100 mL Ocean Spray® Diet Cranberry Juice daily on Day 2-7.

Drug: REL-1017

Placebo

PLACEBO COMPARATOR

100 mL Ocean Spray® Diet Cranberry Juice will be administered as a single oral dose daily for 7 days.

Drug: Placebo

Interventions

REL-1017 DRUG

REL-1017 will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study.

Also known as: d-Methadone

REL-1017 25 mg; REL-1017 50 mg

Placebo DRUG

Placebo will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study.

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males between 18 and 65 years of age, inclusive; and females between 18 and 65 years of age, inclusive, who are \>1 year postmenopausal.
• Diagnosed with recurrent MDD as defined by the Diagnostic and Statistical Manual, Fifth Edition (DSM-5), and confirmed by the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI).
• Diagnosed with a current MDE lasting 8 weeks to 36 months as defined by the DSM-5 and confirmed by the MINI.
• Treated with an adequate dosage of a SSRI, SNRI, or bupropion during the current MDE for at least 8 weeks prior to Screening with the same, adequate dosage for the last 4 weeks. Minimum adequate doses are defined in the (ATRQ). The maximum dose allowed for paroxetine is 40 mg QD, for fluoxetine is 60 mg QD, and for sertraline is 200 mg QD.
• Have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication in the current episode, as defined as \<50% improvement with an antidepressant medication at doses listed on the SAFER Interview Criteria: State versus trait; Assessability; Face validity; Ecological validity; and Rule of three Ps (pervasive, persistent, and pathological).
• Hamilton Depression Rating Scale-17 (HAM-D-17) ≥19 at Screening and Check-in (Day -1).
• BMI between 18.0 and 35.0 kg/m2, inclusive, and a minimum weight of 50.0 kg.
• Per the Investigator's judgment, able to meet all study requirements, including the confined/inpatient portion of the study, adherence with both approved ADT and study drug regimen, and completion of all assessments and all scheduled visits.
• Male patients of reproductive potential must be using and willing to continue using medically acceptable contraception, from Screening and for at least 2 months after the last study drug administration.
• Must be able to read, speak, and understand English and must provide written informed consent prior to the initiation of any protocol-specific procedures.

You may not qualify if:

• 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 patient or the validity of the study results, including torsades de pointes, any bradyarrhythmias, or uncompensated heart failure.
• Chronic use of prescribed opioids (i.e., \>120 days in a 6-month period) up to 6 months prior to Screening or any recreational use of opioids.
• Evidence of clinically significant hepatic or renal impairment, including ALT or AST \>1.5 x upper limit of normal (ULN), bilirubin \>1 x ULN, or endocrine laboratory values (including clinically significant thyroid parameters, i.e., thyroid stimulating hormone \[TSH\], triiodothyronine \[T3\], and thyroxine \[T4\]).
• History or family history of sudden unexplained death or long QT syndrome (measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle).
• Any 12-lead ECG with repeated demonstration of QTc ≥450 msec or a QRS interval \>120 msec at Screening.
• History of clinically diagnosed hypotension requiring treatment.
• History or presence of any condition in which an opioid is contraindicated (e.g., significant respiratory depression, acute or severe bronchial asthma or hypercarbia, bronchitis, or has/is suspected of having paralytic ileus).
• No more than 3 prescribed doses of an opioid within the 6 months prior to Screening and no use at all within the last month.
• Use of an antipsychotic, anticonvulsant, or mood stabilizer, regardless of indication, within the 3 months prior to Screening.
• History of allergy or hypersensitivity to methadone or related drugs (e.g., opioids).
• Any current and primary psychiatric disorder, as defined as a condition that is the primary focus of distress and/or treatment, other than MDD.
• Any lifetime history of bipolar I or II disorder, any psychotic disorder, post-traumatic stress disorder, borderline personality disorder, antisocial personality disorder, obsessive compulsive disorder, eating disorder, intellectual disability, or pervasive developmental disorder.
• History in the past 12 months of a primary diagnosis of anxiety disorder or panic disorder not related to the current MDE.
• Current diagnosis of alcohol or substance use disorder, as defined by DSM-5, at Screening or within the 12 months prior to Screening. Patients with the following diagnoses within the past 12 months, however, may be included at the Investigator's discretion: mild alcohol use disorder, mild cannabis use disorder, and any severity tobacco use disorder.
• A confirmed positive result on the urine drug/alcohol screen at Screening or Check-in. If the urine drug/alcohol screen is positive at Screening, retesting or rescreening may be scheduled with prior approval from the Medical Monitor.

Sponsors & Collaborators

• Relmada Therapeutics, Inc.: lead
• Syneos Health: collaborator

Study Sites (10)

Woodland International Research Group

Little Rock, Arkansas, 72211, United States

Location

Collaborative Neuroscience Network, LLC

Garden Grove, California, 92845-2506, United States

Location

Artemis Institute for Clinical Research

San Diego, California, 92103, United States

Location

Innovative Clinical Research, Inc

Hialeah, Florida, 33012, United States

Location

Atlanta Center for Medical Research

Atlanta, Georgia, 30331, United States

Location

iResearch Atlanta, LLC

Decatur, Georgia, 30030, United States

Location

St. Louis Clinical Trials, LLC

St Louis, Missouri, 63141, United States

Location

Hassman Research Institute

Berlin, New Jersey, 08009, United States

Location

Midwest Clinical Research Center

Dayton, Ohio, 45417-3445, United States

Location

Pillar Clinical Research, LLC

Richardson, Texas, 75080, United States

Location

Related Publications (3)

• Fava M, Stahl S, Pani L, De Martin S, Pappagallo M, Guidetti C, Alimonti A, Bettini E, Mangano RM, Wessel T, de Somer M, Caron J, Vitolo OV, DiGuglielmo GR, Gilbert A, Mehta H, Kearney M, Mattarei A, Gentilucci M, Folli F, Traversa S, Inturrisi CE, Manfredi PL. REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial. Am J Psychiatry. 2022 Feb;179(2):122-131. doi: 10.1176/appi.ajp.2021.21020197. Epub 2021 Dec 22.

  PMID: 34933568 RESULT

• Guidetti C, Serra G, Pani L, Pappagallo M, Maglio G, Martin S, Mattarei A, Folli F, Manfredi PL, Fava M. Subanalysis of Subjective Cognitive Measures From a Phase 2, Double-Blind, Randomized Trial of REL-1017 in Patients With Major Depressive Disorder. Prim Care Companion CNS Disord. 2023 Feb 14;25(1):22m03267. doi: 10.4088/PCC.22m03267.

  PMID: 36821775 RESULT

• Guidetti C, De Martin S, Serra G, Apicella M, Pani L, Pappagallo M, Mattarei A, Folli F, Manfredi P, Fava M. Effect of Time From Onset of Major Depressive Disorder on the Therapeutic Response to Esmethadone (REL-1017). J Clin Psychiatry. 2024 May 13;85(2):22m14735. doi: 10.4088/JCP.22m14735.

  PMID: 38767937 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Depression

Interventions

D-methadone

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Relmada Therapeutics

info@relmada.com

646-876-3459

Study Officials

• Maurizio Fava, MD

  KOL / Advisor

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2017
• First Posted: February 13, 2017
• Study Start: May 11, 2018
• Primary Completion: July 30, 2019
• Study Completion: September 30, 2019
• Last Updated: November 1, 2023
• Results First Posted: March 17, 2021

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (10)