Depressive Disorder, MajorPhase 2NCT03051256
Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD
A Phase 2 study testing REL-1017 in people with Depressive Disorder, Major and Depressive Disorder, Treatment-Resistant, run by Relmada Therapeutics, Inc. at 10 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant
- What is being tested?
- REL-1017
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 62 participants
- Where
- 10 sitesUnited States
- Study dates
- 11 May 2018to 30 Sep 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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.
Who cannot join
- 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.
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- 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).
- Positive test for hepatitis B or HIV. Patients with a positive hepatitis C test may be considered for inclusion with approval from the Medical Monitor.
- 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.
- Patients who, in the Investigator's judgment, are at significant risk for suicide. A patient with a Columbia-Suicide Severity Rating Scale (C-SSRS) ideation score of 4 or 5 within the last 6 months or any suicide attempt within the past year must be excluded, as should a patient with an ideation score of 4 or 5 or any suicide attempt at the Check-in or Baseline Visit.
- Patients with a 20% improvement between Screening and Check-in (Day -1) on the HAM-D-17.
- Patients who did not safely discontinue medications prohibited.
- Patients receiving new onset psychotherapy (individual, group, marriage, or family therapy) within 2 months prior to Screening or plans to start at any time during participation in the study.
- Patients who have received electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or vagus nerve stimulation (VNS) or who have participated in a ketamine study within the last 6 months.
- Patients with any clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, chronic pain, or gastrointestinal disorder. Medical conditions that are minor or well-controlled may be permitted if they will not increase the safety risk to the patient or compromise interpretation of the safety or efficacy endpoints.
- Patients taking fluvoxamine or St. John's Wort.
- Patients who have participated in a clinical study with an investigational medication in the past 6 months, or who have participated in more than 4 clinical studies with investigational medications in the past 2 years.
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
United States10 sites
Atlanta Center for Medical Research
Atlanta, Georgia, 30331
Hassman Research Institute
Berlin, New Jersey, 08009
Midwest Clinical Research Center
Dayton, Ohio, 45417-3445
iResearch Atlanta, LLC
Decatur, Georgia, 30030
Collaborative Neuroscience Network, LLC
Garden Grove, California, 92845-2506
Innovative Clinical Research, Inc
Hialeah, Florida, 33012
Woodland International Research Group
Little Rock, Arkansas, 72211
Pillar Clinical Research, LLC
Richardson, Texas, 75080
Artemis Institute for Clinical Research
San Diego, California, 92103
St. Louis Clinical Trials, LLC
St Louis, Missouri, 63141
About this study
Official title: Phase 2a Multicenter Randomized Double-Blind Placebo-Controlled Study to Assess the Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing of REL-1017 as Adjunctive Therapy in the Treatment of Pts Diagnosed With MDD
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.
Read the detailed description
Currently available medications have proven to be useful for the treatment of depression, but also have limitations including low response rates, a significant number of treatment resistant patients, and time-lag for response, which emphasizes a major unmet need for more efficacious and faster-acting antidepressants. Recent studies have demonstrated that ketamine, a non-competitive glutamate-N-methyl-D-Aspartate (NMDA) receptor antagonist, produces rapid onset (2 hours) and long-lasting (7 days) antidepressant actions in treatment resistant patients. This rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, represents a significant finding in the field of depression.
Racemic methadone, the 50/50 combination of d-methadone and l-methadone, has been in widespread use for decades and has been studied extensively. Methadone is currently approved for use in the management of severe pain, detoxification treatment of opioid addiction, and maintenance treatment of opioid addiction.
The results of a study evaluating the receptor binding profiles of racemic methadone and its stereoisomers suggest that d-methadone does not essentially contribute to the opioid effect of racemic methadone and that it has a 10 times lower affinity for the mu1, mu2, and delta opioid receptors compared to l-methadone. Racemic methadone and its d- and l isomers exhibit similar affinities for the non-competitive binding site of the NMDA receptor and are non-competitive NMDA receptor antagonists.
In the forced swim test, a rodent behavioral model of antidepressant activity, both ketamine and d-methadone at all doses tested significantly decreased the immobility of the rats compared to the vehicle suggesting antidepressant like activity. Neither drug increased spontaneous locomotor activity.
Relmada has conducted 2 clinical studies to identify the dose levels of REL-1017 (d-methadone) that have little to no opioid effects and that are expected to possess NMDA antagonistic properties for the evaluation of oral REL-1017 in the treatment of MDD and neuropathic pain conditions. Initial Phase 1 single ascending dose and multiple ascending dose clinical studies of REL-1017 were designed to evaluate the safety and tolerance of the pure d methadone isomer in healthy opioid-naïve subjects and identify a safe and potentially effective dose range in this population. These studies showed that REL-1017 was safe and well-tolerated at single oral doses up to 150 mg (maximum tolerated dose) and up to 75 mg administered once daily for 10 days in healthy opioid-naïve subjects.
The pre-clinical and previous clinical experience with REL-1017 (d-methadone) provided the basis for the initiation of the present study, which will extend the evaluation of the safety, tolerability, and PK of REL-1017 at 2 doses with repeated administration to depressed patients. Since REL-1017 is proposed for use as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD), the patients will be male adults with MDD who are diagnosed with a current depressive episode who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication.
Based on the safety data from Protocol REL-1017-111, single doses of 5 mg, 20 mg, 60 mg, 100 mg, and 150 mg of REL-1017 or placebo were well tolerated. The results of Protocol REL-1017-112 evaluated 10 days of dosing with 25 mg, 50 mg and 75 mg of REL-1017 or placebo, and no impact on safety was observed. In spite of the confirmed dose proportionality, the comparison of concentration and exposure between the 50 mg and 75 mg REL-1017 treatment groups demonstrated only slight differences. Consequently, 25 mg and 50 mg doses were chosen for administration in Protocol REL-1017-202 as single daily doses over a period of 7 days.
Thus, as a single isomer of racemic methadone, d-methadone has been shown to possess NMDA antagonist properties with virtually no opioid activity or ketamine-like toxicities at the expected therapeutic doses.
In this study, adult male patients with MDD who are diagnosed with a current MDE and who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication will be randomized to study drug in a 1:1:1 ratio. Approximately 15 patients each will receive REL-1017 25 mg, REL-1017 50 mg, or placebo once daily for 7 days. Endpoints include assessments of safety, tolerability, efficacy and pharmacokinetics of REL-1017. Patients will be required to stay in the clinic for 10 days and will then be followed as an outpatient for 12 additional days.
- Being tested
- REL-1017, Placebo
- Keywords
- REL-1017, d-Methadone, Methadone, Depression, Refractory Depression, Antidepressant, Adjunctive Treatment, NMDA Receptor Antagonist, Excitatory Amino Acid Antagonist, Glutamate Antagonist
- Medical subject headings
- Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
REL-1017Drug
Also called d-Methadone
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 21 days
Secondary outcomes (15)
ECG Parameters [Safety]
12-Lead ECGs will be performed and reported at Screening; at Check In (Day -1); Days 1 through 9; and at Day 14.
Measured: 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]
The C-SSRS will be administered and reported at Screening and Check In (Day -1); and at Days 1, 2, 8, 9 and 14.
The C-SSRS is routinely used to quantify the severity of suicidal ideation and behavior. Both the ideation and behavior subscales are sensitive to change over time.
The scale identifies behaviors that may be indicative of an individual's intent to commit suicide. This measure contains 6 "yes" or "no" questions in which respondents are asked to indicate whether they have experienced several thoughts or feelings relating to suicide over the past month. Each question addresses a different component of the respondent's suicide ideation severity: (1) Desire to be dead; (2) Suicidal thoughts; (3) Consideration of suicide methods; (4) Formed intent to commit suicide; (5) Completed suicide plan; and (6) Initiated suicide plan. A higher score indicates a higher intensity of suicidal ideation.
Measured: Day -1, Day 1, Day 2, Day 8, Day 9 and Day 14
Montgomery-Asberg Depression Scale (MADRS)
Montgomery-Asberg Depression Scale (MADRS) will be administered and reported on Days 4, 7, and 14.
The MADRS questionnaire includes questions on the following symptoms: (1) Apparent sadness; (2) Reported sadness; (3) Inner tension; (4) Reduced sleep; (5) Reduced appetite; (6) Concentration difficulties; (7) Lassitude; (8) Inability to feel; (9) Pessimistic thoughts; (10) Suicidal thoughts.
A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 with scores above 34 indicating severe depression. In Study REL-1017-202, the MADRS was administered using the Structured Interview Guide for the MADRS (SIGMA).
A negative change from baseline indicates improvement.
Measured: Change from Baseline to Day 7
Montgomery-Asberg Depression Scale (MADRS)
Montgomery-Asberg Depression Scale (MADRS) will be administered and reported on Days 4, 7, and 14.
The MADRS questionnaire includes questions on the following symptoms: (1) Apparent sadness; (2) Reported sadness; (3) Inner tension; (4) Reduced sleep; (5) Reduced appetite; (6) Concentration difficulties; (7) Lassitude; (8) Inability to feel; (9) Pessimistic thoughts; (10) Suicidal thoughts.
A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 with scores above 34 indicating severe depression. In Study REL-1017-202, the MADRS was administered using the Structured Interview Guide for the MADRS (SIGMA).
A negative change from baseline indicates improvement.
Measured: Change from Baseline to Day 14
Symptoms of Depression Questionnaire (SDQ)
Symptoms of Depression Questionnaire (SDQ) will be administered and reported on Days 4, 7, and 14.
The SDQ is a 44-item, self-report scale designed to measure the severity of symptoms across several subtypes of depression. The SDQ was developed to more fully capture the heterogeneity of symptom presentations of depressive disorders than current, widely used scales for MDD. The SDQ includes items that inquire about an extensive number of depressive symptoms beyond the ones included in other commonly used scales. The 44 SDQ items are rated on a 6-point scale. The total score is the sum of 44 items and can range from 44 to 264. A negative change from baseline indicates improvement.
1 = Better than Normal; 2= Normal; 3= Minimally Sad; 4= Moderately Sad; 5= Markedly Sad; 6= Extremely Sad
Measured: Change from Baseline to Day 7
Symptoms of Depression Questionnaire (SDQ)
Symptoms of Depression Questionnaire (SDQ) will be administered and reported on Days 4, 7, and 14.
The SDQ is a 44-item, self-report scale designed to measure the severity of symptoms across several subtypes of depression. The SDQ was developed to more fully capture the heterogeneity of symptom presentations of depressive disorders than current, widely used scales for MDD. The SDQ includes items that inquire about an extensive number of depressive symptoms beyond the ones included in other commonly used scales. The 44 SDQ items are rated on a 6-point scale. The total score is the sum of 44 items and can range from 44 to 264. A negative change from baseline indicates improvement.
1 = Better than Normal; 2= Normal; 3= Minimally Sad; 4= Moderately Sad; 5= Markedly Sad; 6= Extremely Sad
Measured: Change from Baseline to Day 14
Clinical Global Impressions of Severity (CGI-S)
Clinical Global Impressions of Severity (CGI-S) will be administered and reported on Days 4, 7, and 14.
The CGI-S is a standard method used in clinical studies to quantify and track patient progress and treatment response over time. The scale is composed of 7 ratings: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. The score ranges from 1 to 7, and a lower CGI-S score indicates lower levels of depression.
Measured: Change from Baseline to Day 7
Clinical Global Impressions of Severity (CGI-S)
Clinical Global Impressions of Severity (CGI-S) will be administered and reported on Days 4, 7, and 14.
The CGI-S is a standard method used in clinical studies to quantify and track patient progress and treatment response over time. The scale is composed of 7 ratings: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. The score ranges from 1 to 7, and a lower CGI-S score indicates lower levels of depression.
Measured: Change from Baseline to Day 14
Clinical Global Impressions of Improvement (CGI-I)
Clinical Global Impressions of Improvement (CGI-I) will be administered and reported at Days 4, 7 and 14.
The CGI-I is a standard method used in clinical studies to quantify and track patient change over time. The scale is composed of 7 ratings: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse. The score ranges from 1 to 7, and a lower CGI-I score indicates greater improvement in symptoms.
Measured: Change from Baseline to Day 7
Clinical Global Impressions of Improvement (CGI-I)
Clinical Global Impressions of Improvement (CGI-I) will be administered and reported at Days 4, 7 and 14.
The CGI-I is a standard method used in clinical studies to quantify and track patient change over time. The scale is composed of 7 ratings: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse. The score ranges from 1 to 7, and a lower CGI-I score indicates greater improvement in symptoms.
Measured: Change from Baseline to Day 14
Maximum Observed Plasma Concentration (Cmax) [Pharmacokinetic]
The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Measured: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)
Area Under the Plasma Concentration-time Curve From Time Zero Until the Dosing Interval of 24 Hours (AUCtau) [Pharmacokinetic]
The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Measured: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)
Time to Maximum Observed Plasma Concentration (Tmax) [Pharmacokinetic]
The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Measured: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) [Pharmacokinetic]
The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Measured: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)
Apparent Terminal Elimination Half-life (t½) [Pharmacokinetic]
The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Measured: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24) and Day 7 (hour 24, 48, and 168 post last dose)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2017
- Study start11 May 2018
- Primary completion30 Jul 2019
- Study completion30 Sep 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Depressive Disorder, MajorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- Relmada Therapeutics, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Syneos Health
- Responsible party
- Sponsor
- Investigators
- Maurizio Fava, MD, Study chair, KOL / Advisor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03051256
- Sponsor's protocol ID
- REL-1017-202
- Status last verified
- Oct 2023
- First submitted
- 3 Feb 2017
- Last updated
- 1 Nov 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 34933568Guidetti 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.
PubMed 36821775Guidetti 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.
PubMed 38767937
Study at a glance
From the registry record, last updated by the sponsor on 1 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2a Multicenter Randomized Double-Blind Placebo-Controlled Study to Assess the Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing of REL-1017 as Adjunctive Therapy in the Treatment of Pts Diagnosed With MDD
- ClinicalTrials.gov ID
- NCT03051256
- Acronym / sponsor ID
- REL-1017-202
- Keywords
- REL-1017, d-Methadone, Methadone, Depression, Refractory Depression, Antidepressant, Adjunctive Treatment, NMDA Receptor Antagonist
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- Relmada Therapeutics, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Syneos Health
- Study start
- 11 May 2018 (actual)
- Primary completion
- 30 Jul 2019 (actual)
- Study completion
- 30 Sep 2019 (actual)
- First posted
- 13 Feb 2017 (actual)
- Results
- Posted 17 Mar 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Currently available medications have proven to be useful for the treatment of depression, but also have limitations including low response rates, a significant number of treatment resistant patients, and time-lag for response, which emphasizes a major unmet need for more efficacious and faster-acting antidepressants. Recent studies have demonstrated that ketamine, a non-competitive glutamate-N-methyl-D-Aspartate (NMDA) receptor antagonist, produces rapid onset (2 hours) and long-lasting (7 days) antidepressant actions in treatment resistant patients. This rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, represents a significant finding in the field of depression.
Racemic methadone, the 50/50 combination of d-methadone and l-methadone, has been in widespread use for decades and has been studied extensively. Methadone is currently approved for use in the management of severe pain, detoxification treatment of opioid addiction, and maintenance treatment of opioid addiction.
The results of a study evaluating the receptor binding profiles of racemic methadone and its stereoisomers suggest that d-methadone does not essentially contribute to the opioid effect of racemic methadone and that it has a 10 times lower affinity for the mu1, mu2, and delta opioid receptors compared to l-methadone. Racemic methadone and its d- and l isomers exhibit similar affinities for the non-competitive binding site of the NMDA receptor and are non-competitive NMDA receptor antagonists.
In the forced swim test, a rodent behavioral model of antidepressant activity, both ketamine and d-methadone at all doses tested significantly decreased the immobility of the rats compared to the vehicle suggesting antidepressant like activity. Neither drug increased spontaneous locomotor activity.
Relmada has conducted 2 clinical studies to identify the dose levels of REL-1017 (d-methadone) that have little to no opioid effects and that are expected to possess NMDA antagonistic properties for the evaluation of oral REL-1017 in the treatment of MDD and neuropathic pain conditions. Initial Phase 1 single ascending dose and multiple ascending dose clinical studies of REL-1017 were designed to evaluate the safety and tolerance of the pure d methadone isomer in healthy opioid-naïve subjects and identify a safe and potentially effective dose range in this population. These studies showed that REL-1017 was safe and well-tolerated at single oral doses up to 150 mg (maximum tolerated dose) and up to 75 mg administered once daily for 10 days in healthy opioid-naïve subjects.
The pre-clinical and previous clinical experience with REL-1017 (d-methadone) provided the basis for the initiation of the present study, which will extend the evaluation of the safety, tolerability, and PK of REL-1017 at 2 doses with repeated administration to depressed patients. Since REL-1017 is proposed for use as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD), the patients will be male adults with MDD who are diagnosed with a current depressive episode who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication.
Based on the safety data from Protocol REL-1017-111, single doses of 5 mg, 20 mg, 60 mg, 100 mg, and 150 mg of REL-1017 or placebo were well tolerated. The results of Protocol REL-1017-112 evaluated 10 days of dosing with 25 mg, 50 mg and 75 mg of REL-1017 or placebo, and no impact on safety was observed. In spite of the confirmed dose proportionality, the comparison of concentration and exposure between the 50 mg and 75 mg REL-1017 treatment groups demonstrated only slight differences. Consequently, 25 mg and 50 mg doses were chosen for administration in Protocol REL-1017-202 as single daily doses over a period of 7 days.
Thus, as a single isomer of racemic methadone, d-methadone has been shown to possess NMDA antagonist properties with virtually no opioid activity or ketamine-like toxicities at the expected therapeutic doses.
In this study, adult male patients with MDD who are diagnosed with a current MDE and who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication will be randomized to study drug in a 1:1:1 ratio. Approximately 15 patients each will receive REL-1017 25 mg, REL-1017 50 mg, or placebo once daily for 7 days. Endpoints include assessments of safety, tolerability, efficacy and pharmacokinetics of REL-1017. Patients will be required to stay in the clinic for 10 days and will then be followed as an outpatient for 12 additional days.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| REL-1017 25 mg | Experimental | Drug: REL-1017REL-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. |
| REL-1017 50 mg | Experimental | Drug: REL-1017REL-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. |
| Placebo | Placebo comparator | Drug: Placebo100 mL Ocean Spray® Diet Cranberry Juice will be administered as a single oral dose daily for 7 days. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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).
Key exclusion criteria (24 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| REL-1017Also: d-MethadoneREL-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. | Drug | REL-1017 25 mg, REL-1017 50 mg |
| PlaceboPlacebo 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. | Drug | Placebo |
Primary outcome
Incidence of Treatment Emergent Adverse Events (AEs) [Safety and Tolerability]
Time frame: 21 days
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).
15 secondary outcomes
ECG Parameters [Safety]
Time frame: 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]
Time frame: Day -1, Day 1, Day 2, Day 8, Day 9 and Day 14
Montgomery-Asberg Depression Scale (MADRS)
Time frame: Change from Baseline to Day 7
Montgomery-Asberg Depression Scale (MADRS)
Time frame: Change from Baseline to Day 14
Symptoms of Depression Questionnaire (SDQ)
Time frame: Change from Baseline to Day 7
Symptoms of Depression Questionnaire (SDQ)
Time frame: Change from Baseline to Day 14
Clinical Global Impressions of Severity (CGI-S)
Time frame: Change from Baseline to Day 7
Clinical Global Impressions of Severity (CGI-S)
Time frame: Change from Baseline to Day 14
Clinical Global Impressions of Improvement (CGI-I)
Time frame: Change from Baseline to Day 7
Clinical Global Impressions of Improvement (CGI-I)
Time frame: Change from Baseline to Day 14
Maximum Observed Plasma Concentration (Cmax) [Pharmacokinetic]
Time frame: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)
Area Under the Plasma Concentration-time Curve From Time Zero Until the Dosing Interval of 24 Hours (AUCtau) [Pharmacokinetic]
Time frame: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)
Time to Maximum Observed Plasma Concentration (Tmax) [Pharmacokinetic]
Time frame: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) [Pharmacokinetic]
Time frame: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)
Apparent Terminal Elimination Half-life (t½) [Pharmacokinetic]
Time frame: Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24) and Day 7 (hour 24, 48, and 168 post last dose)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Nov 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 34933568Fava 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.
- Results publication: PubMed 36821775Guidetti 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.
- Derived from this study: PubMed 38767937Guidetti 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maurizio Fava, MD study chair
KOL / Advisor
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing REL-1017 in people with Depressive Disorder, Major and Depressive Disorder, Treatment-Resistant, run by Relmada Therapeutics, Inc. at 10 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Mar 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Treatment Emergent Adverse Events (AEs) [Safety and Tolerability] (time frame: 21 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03051256, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2023.