Major Depressive DisorderPhase 3Reliance INCT04688164

A Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment for Major Depressive Disorder (MDD)

A Phase 3 study testing REL-1017 in people with Major Depressive Disorder, run by Relmada Therapeutics, Inc. at 11 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Major Depressive Disorder
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: 227 participants
Where: 11 sitesUnited States
Study dates: 8 Jan 2021to 10 Nov 2022
Phase: Phase 3
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

Adults 18 to 65 years, inclusive.
Diagnosed with Major Depressive Disorder (MDD) based on structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, DSM-5 (SCID-5) for MDD.
Current major depressive episode.
With inadequate response to 1-3 first-line antidepressants administered at an adequate and stable dose

Who cannot join

Any current and primary psychiatric disorder other than Major Depressive Disorder.
Severe alcohol or substance use disorder.
History of bipolar I and II disorder, psychosis, and/or mania.
Acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to complete or participate in this clinical study.
Prior participation in a ketamine, esketamine, dextromethorphan or any other NMDAR- antagonist study, or received esketamine at any time.

Trial locations and contacts

11 sites in 1 country.

City, postcode or hospital

11 sites in 1 country

United States11 sites

Relmada Site
Austin, Texas, 78737
Relmada Site
Boston, Massachusetts, 02116
Relmada Site
Chicago, Illinois, 60634
Relmada Site
Cincinnati, Ohio, 45215
Relmada Site
Decatur, Georgia, 30030
Relmada Site
Miami, Florida, 33175
Relmada Site
Miami Springs, Florida, 33166
Relmada Site
New York, New York, 10128
Relmada Site
O'Fallon, Missouri, 63368
Relmada Site
Palm Bay, Florida, 32905
Relmada Site
Watertown, Massachusetts, 02472

Other trials in United States

About this study

Official title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment of Major Depressive Disorder (The RELIANCE-I Study)

This is an outpatient, 2-arm, Phase 3, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of REL-1017 once daily (QD) as an adjunctive treatment of Major Depressive Disorder. Study participants will continue to take their current antidepressant therapy in addition to the study drug or placebo for the duration of the treatment period.

Conditions: Major Depressive Disorder
Being tested: REL-1017, Placebo
Keywords: REL-1017
Medical subject headings: Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

REL-1017Drug
Also called esmethadone
REL-1017 tablet
PlaceboDrug
Placebo tablet

Study groups in NCT04688164
Study group	Role	What they receive
REL-1017	Experimental	A 75 mg REL-1017 loading dose (three 25 mg REL-1017 tablets) will be administered on Day-1 of the 28-day treatment period. From Day-2 to Day-28, participants will take 25 mg REL-1017 in addition to their ongoing antidepressant. Receives: Drug: REL-1017
Placebo	Placebo comparator	Three tablets of matching placebo will be administered on Day-1 of the 28-day treatment period. From Day-2 to Day-28, participants will take 1 placebo tablet in addition to their ongoing antidepressant. Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Change in the MADRS10 Total Score From Baseline to Day 28
Therapeutic efficacy of REL-1017 as adjunctive treatment versus placebo in the Montgomery-Asberg Depression Rating Scale (MADRS10)
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.
A negative change from baseline indicates improvement.
Measured: Day 28

Secondary outcomes (2)

MADRS10 Remission Rate (Total Score ≤10) at Day 28
Therapeutic remission rate with REL-1017 as adjunctive treatment versus placebo in the Montgomery-Asberg Depression Rating Scale (MADRS10). Remission is defined as MADRS10 Total Score ≤10 at Day 28. A higher percentage of remission indicates a higher percentage of subjects with MADRS10 Total Score ≤10 at Day 28.
Measured: Day 28
MADRS10 Response Rate (Improvement ≥50% Compared With Total Baseline Score) at Day 28
Therapeutic response to REL-1017 as adjunctive treatment versus placebo in the Montgomery-Asberg Depression Rating Scale (MADRS10). Response rate is defined as an improvement ≥50% compared with total Baseline MADRS10 score.
Measured: Day 28

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

8 Jan 202110 Nov 2022

First posted29 Dec 2020
Study start8 Jan 2021
Primary completion1 Nov 2022
Study completion10 Nov 2022

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 (2)Papers the sponsor has linked to this study.
Other trials for Major Depressive DisorderStudies 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 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 227 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04688164
Sponsor's protocol ID: REL-1017-301
Acronym: Reliance I
Status last verified: Aug 2024
First submitted: 7 Dec 2020
Last updated: 27 Aug 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Expanded access: Available

Publications

Fava M, Stahl SM, Pani L, De Martin S, Cutler AJ, Maletic V, Gorodetzky CW, Vocci FJ, Sapienza FL, Kosten TR, Kroger C, Champasa P, O'Gorman C, Guidetti C, Alimonti A, Comai S, Mattarei A, Folli F, Bushnell D, Traversa S, Inturrisi CE, Manfredi PL, Pappagallo M. Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial. J Clin Psychiatry. 2024 Jun 17;85(3):24m15265. doi: 10.4088/JCP.24m15265.
PubMed 38917366
Guidetti C, Papakostas GI, Stahl S, Pani L, De Martin S, Mattarei A, Comai S, Kroger C, Champasa P, Gorodetzky CW, Vocci FJ, Kosten TR, Bushnell D, Kappler M, Folli F, Inturrisi CE, Pappagallo M, Manfredi PL, Fava M. Depression severity and efficacy outcomes: post hoc analyses from a phase 3 trial of esmethadone for the adjunctive treatment of major depressive disorder with inadequate response to standard antidepressants. Int Clin Psychopharmacol. 2026 Jul 1;41(4):213-224. doi: 10.1097/YIC.0000000000000618. Epub 2026 Feb 17.
PubMed 41749468

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 27 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment of Major Depressive Disorder (The RELIANCE-I Study)
ClinicalTrials.gov ID: NCT04688164
Acronym / sponsor ID: Reliance I / REL-1017-301
Conditions: Major Depressive Disorder
Keywords: REL-1017
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 227 participants (actual)
Lead sponsor: Relmada Therapeutics, Inc.Industry (pharma, biotech, devices)
Study start: 8 Jan 2021 (actual)
Primary completion: 1 Nov 2022 (actual)
Study completion: 10 Nov 2022 (actual)
First posted: 29 Dec 2020 (actual)
Results: Posted 26 Mar 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
REL-1017	Experimental	Drug: REL-1017A 75 mg REL-1017 loading dose (three 25 mg REL-1017 tablets) will be administered on Day-1 of the 28-day treatment period. From Day-2 to Day-28, participants will take 25 mg REL-1017 in addition to their ongoing antidepressant.
Placebo	Placebo comparator	Drug: PlaceboThree tablets of matching placebo will be administered on Day-1 of the 28-day treatment period. From Day-2 to Day-28, participants will take 1 placebo tablet in addition to their ongoing antidepressant.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (4 listed)

Adults 18 to 65 years, inclusive.
Diagnosed with Major Depressive Disorder (MDD) based on structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, DSM-5 (SCID-5) for MDD.
Current major depressive episode.
With inadequate response to 1-3 first-line antidepressants administered at an adequate and stable dose

Key exclusion criteria (5 listed)

Any current and primary psychiatric disorder other than Major Depressive Disorder.
Severe alcohol or substance use disorder.
History of bipolar I and II disorder, psychosis, and/or mania.
Acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to complete or participate in this clinical study.
Prior participation in a ketamine, esketamine, dextromethorphan or any other NMDAR- antagonist study, or received esketamine at any time.

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: esmethadoneREL-1017 tablet	Drug	REL-1017
PlaceboPlacebo tablet	Drug	Placebo

Primary outcome

Change in the MADRS10 Total Score From Baseline to Day 28
Time frame: Day 28
Therapeutic efficacy of REL-1017 as adjunctive treatment versus placebo in the Montgomery-Asberg Depression Rating Scale (MADRS10) 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. A negative change from baseline indicates improvement.

2 secondary outcomes

MADRS10 Remission Rate (Total Score ≤10) at Day 28
Time frame: Day 28
MADRS10 Response Rate (Improvement ≥50% Compared With Total Baseline Score) at Day 28
Time frame: Day 28

Results and safety

Results posted to the registry on 26 Mar 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
REL-1017	113	106
Placebo	114	99

Primary outcome: Change in the MADRS10 Total Score From Baseline to Day 28

Time frame: Day 28. Mean (Standard Deviation). Unit: score on a scale

Measure	REL-1017 25 mg n = 103	Placebo n = 88
Value	-15.1 (11.3)	-12.9 (10.4)

Population analysed: Full Analysis Set: defined as all subjects who received at least one dose of study medication and were assessed for the primary efficacy endpoint at both Baseline and Day 28

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: TEAE that starts or worsens at any time after initiation of study drug collected up to 14 days post treatment (Day 42).. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
REL-1017 25 mg	3 of 113 (2.7%)	34 of 113 (30.1%)	0 of 113
Placebo	0 of 114 (0%)	34 of 114 (29.8%)	0 of 114

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 38917366Fava M, Stahl SM, Pani L, De Martin S, Cutler AJ, Maletic V, Gorodetzky CW, Vocci FJ, Sapienza FL, Kosten TR, Kroger C, Champasa P, O'Gorman C, Guidetti C, Alimonti A, Comai S, Mattarei A, Folli F, Bushnell D, Traversa S, Inturrisi CE, Manfredi PL, Pappagallo M. Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial. J Clin Psychiatry. 2024 Jun 17;85(3):24m15265. doi: 10.4088/JCP.24m15265.
Derived from this study: PubMed 41749468Guidetti C, Papakostas GI, Stahl S, Pani L, De Martin S, Mattarei A, Comai S, Kroger C, Champasa P, Gorodetzky CW, Vocci FJ, Kosten TR, Bushnell D, Kappler M, Folli F, Inturrisi CE, Pappagallo M, Manfredi PL, Fava M. Depression severity and efficacy outcomes: post hoc analyses from a phase 3 trial of esmethadone for the adjunctive treatment of major depressive disorder with inadequate response to standard antidepressants. Int Clin Psychopharmacol. 2026 Jul 1;41(4):213-224. doi: 10.1097/YIC.0000000000000618. Epub 2026 Feb 17.
Study HomepageLink provided by the sponsor.

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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.

Marco Pappagallo, MD study director

Relmada Therapeutics

11 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing REL-1017 in people with Major Depressive Disorder, run by Relmada Therapeutics, Inc. at 11 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 4 inclusion and 5 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 27 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

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 26 Mar 2024). 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?

Change in the MADRS10 Total Score From Baseline to Day 28 (time frame: Day 28). 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 NCT04688164, which also lists 2 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 27 Aug 2024.