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Treatment Resistant DepressionPhase 2ENLIGHTENNCT05113771

A Biomarker-Guided, Randomized, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With TRD

A Phase 2 study testing Liafensine in people with Treatment Resistant Depression, run by Denovo Biopharma LLC at 45 sites in 2 countries.

Completed

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

Official record
Search all trials

Trial summary

This study was conducted as a randomized, double-blind, placebo-controlled, multi-center Phase 2b study. Approximately 180 subjects with treatment resistant depression who meet all eligibility criteria will be enrolled. Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Treatment Resistant Depression
What is being tested?
Liafensine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
197 participants
Where
45 sitesin 2 countries
Study dates
29 Jun 2022to 5 Mar 2024
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 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Provide signed informed consent which includes pharmacogenomic (PGx) testing.
  • Have a diagnosis of MDD without psychotic features, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, based on clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI).
  • Have a history of TRD within the past 5 years as documented by the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) (5-year version). That is, within the past 5 years study participants must have had a clinically meaningful inadequate response (estimated < 50% improvement per Investigator/patient consensus and documented by the Investigator) to at least two treatment courses with antidepressant regimens. These must involve at least two different pharmacologic treatment classes* and have been given at accepted therapeutic doses for an adequate duration (at least 6 weeks). One of these treatment failures must have occurred within the current episode.
  • Note: Non-pharmacological treatment (eg, cognitive behavioral therapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagus nerve stimulation, acupuncture) are not counted as treatment regimen.
  • To be eligible, patients must have DGM4 genotype results obtained from the designated Clinical Laboratory Improvement Amendments (CLIA) lab, and all eligible DGM4-positive patients and about 20% DGM4-negative patients will be randomly included by an IRT system in order to achieve the appropriate randomization ratio of DGM4-positive vs negative patients.
  • Pregnancy conception limitations
Show all 12Show fewer
  • Female patients must be postmenopausal or surgically sterile or, if of childbearing potential and the partner is not vasectomized (6 months minimum), must agree to use a medically acceptable form of contraception from the time of signing the informed consent form (ICF) through at least 60 days following the last administration of study drug. If only the barrier method is used, a double barrier must be employed. Postmenopausal women must have had ≥ 24 months of spontaneous amenorrhea. Surgically sterile women are defined as those who have had a hysterectomy, bilateral ovariectomy, or bilateral tubal ligation. All women of childbearing potential must have a negative pregnancy test result before administration of study drug.
  • Male patients must be biologically incapable of having children (eg, vasectomized) or must agree to use the above forms of birth control for themselves and their partner from the time of signing the informed consent form through at least 120 days following the last administration of study drug.
  • Be fluent in the local language.
  • Male or female aged 18 to 70, inclusive, at time of enrollment.
  • Have a HAMD-17 total score ≥ 21 at screening.
  • Be willing to discontinue the use of antidepressant drugs (including over-the-counter medications to treat depression [eg, St John's Wort]) at least 5 half-lives (or at least 1 week for herbal or other over-the-counter medications for depression) prior to baseline (Day -1). For fluoxetine, a washout period of at least 3 weeks for ≤ 20 mg/day and at least 4 weeks for > 20 mg/day is required.

Who cannot join

  • Prior participation in a study with liafensine
  • Used any investigational drug product, device, or biologic within 6 months or five half-lives (whichever is longer) prior to baseline (Day -1).
  • A positive pregnancy test result or currently breastfeeding.
  • Clinically significant illness (including chronic, persistent, or acute infection), medical/surgical procedure, or trauma within 30 days prior to screening or between screening and baseline (Day 1) as determined by the investigator.
  • A history or presence of a clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, respiratory, immunologic, hematologic, dermatologic, or neurologic abnormality, or any other condition, that in the investigator's opinion, represent potential risk to the patient's safety, full participation in the study, or affect the absorption, distribution, metabolism, or excretion of liafensine.
  • Presence of autoimmune hepatitis, primary sclerosing cholangitis, untreated hepatitis C, active hepatitis B, or any other uncontrolled or unstable liver disease according to local guidance.
Show all 41Show fewer
  • Uncontrolled human immunodeficiency virus (HIV) infection according to local guidance.
  • Uncontrolled abnormal thyroid function according to local guidance.
  • One or more clinical laboratory evaluations are outside the reference range, at screening, that are in the investigator's opinion, of potential risk to the patient's safety.
  • Has at the Screening Visit:
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 1.5x the upper limit of normal (ULN) at screening.
  • Total bilirubin (TBL) > 2 mg/dL (34.2 μmol/L) at screening, unless there is an explained indirect hyperbilirubinemia, eg, Gilbert's syndrome.
  • Alkaline phosphatase (ALP) > 1.5x the ULN at screening. Note: Laboratory tests can be repeated to see if values return to normal range, but any such laboratory abnormality must be resolved by the Baseline Visit (Day -1).
  • Clinically significant vital sign abnormality at screening. This includes, but is not limited to, the following, in the supine (after at least 5 min rest) and standing (after 1 min and 3 min standing): systolic blood pressure ≥ 140 mmHg; diastolic blood pressure ≥ 90 mmHg; or heart rate < 50 or > 90 beats per minute. If the initial blood pressure is ≥ 140/90 mmHg, the lowest value from up to 3 additional attempts, which also must not be ≥ 140/90 mmHg, should be used. Patients with symptomatic orthostatic hypotension, at the discretion of investigator, will be excluded.
  • Corrected QT interval measurement according to the Fridericia rule (QTcF) > 450 msec for men and > 470 msec for women during controlled rest at screening, or history of long-QT syndrome.
  • ECGs containing any of the following readings:
  • Left bundle branch block
  • Right bundle branch block with QRS duration > 140 ms
  • Intraventricular conduction defect with QRS duration > 140 ms
  • Long QT syndrome
  • History of seizure, other than childhood febrile seizures.
  • History of clinically significant head trauma, including closed head injury with loss of consciousness, that is, in the opinion of the investigator, likely to affect central nervous system function.
  • History of clinically significant symptomatic orthostatic hypotension (ie, postural syncope).
  • History of narrow angle glaucoma.
  • History of cancer within 2 years prior to screening or between screening and baseline (Day -1), except for non-metastatic basal and/or squamous cell carcinoma of the skin.
  • Use of prescription or nonprescription medications for attention-deficit hyperactivity disorder (ADHD), narcolepsy, or cognitive enhancement (eg, methylphenidate, atomoxetine, modafinil, ginkgo biloba, and huperzine A) within 30 days prior to screening or between screening and baseline (Day -1).
  • Regular consumption of (eg, more days than not) excessive quantities of xanthine-containing beverages (eg, more than five cups of coffee or the equivalent per day) within 30 days prior to screening or between screening and baseline (Day -1).
  • Urine drug screen (UDS) positive for a drug of abuse, with the exception of cannabis in countries where it is legally available (see Table 3 for list of drugs of abuse). Where legal, prior use of cannabis is permitted provided the patient agrees to abstain from smoking or ingesting cannabis or cannabis products during the study.
  • Use of potent inducers of CYP3A4 (eg, rifampin, rifabutin, phenytoin, carbamazepine, or phenobarbital) within 2 weeks prior to baseline (Day-1).
  • Current diagnosis or history of a psychotic disorder, MDD with psychotic features, manic or hypomanic episode of bipolar or related disorders.
  • Current diagnosis of anxiety disorder (if primary), post-traumatic stress disorder, obsessive compulsive disorder (if primary), intellectual disability (DSM-5 diagnostic code 319), borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder according to the DSM-5 criteria, or any other psychiatric or neurologic disorder or symptom due to a general medical condition, that, in the judgement of the investigator, could pose undue risk to the patient or compromise the study.
  • Hospitalized or discharged from psychiatric ward within 8 weeks prior to the screening visit and planned hospitalization for any condition(s) during the study.
  • Moderate or severe alcohol use disorder or other substance use disorder (except nicotine or caffeine), within 6 months prior to screening, according to the DSM-5 criteria.
  • Significant risk of suicide determined by:
  • Acute suicidality as evidenced by answering "yes" to Question 5 ("In the Past Year") on the C-SSRS, indicating active suicidal ideation with specific plan and intent for suicide, at screening, or baseline (Day -1); or
  • History of suicidal behavior as indicated by a "yes" response on the Suicidal Behavior section of the C-SSRS ("In the past year") or
  • A score ≥ 5 on Item 10 (suicidal thoughts) of the MADRS at screening or baseline (Day -1); or
  • Has attempted suicide within 6 months prior to the initial screening visit.
  • Previous allogenic bone marrow transplant.
  • Received non-leukocyte-depleted whole blood transfusion within 4 months prior to PGx testing at Screening.
  • Currently employed by the sponsor or by a clinical trial site participating in this study, or a first-degree relative of an employee of the sponsor or of an employee at a participating clinical trial site.

Trial locations and contacts

45 sites in 2 countries.

45 sites in 2 countries

United States41 sites

  • IMA Clinical Research

    Albuquerque, New Mexico, 87109

  • Lehigh Center for Clinical Research, LLC

    Allentown, Pennsylvania, 18104

  • CenExel Atlanta Center for Medical Research

    Atlanta, Georgia, 30331

  • Pharmasite Research, Inc.

    Baltimore, Maryland, 21208

  • Neurobehavioral Medicine Group

    Bloomfield, Michigan, 48302

  • Boston Clinical Trials & Medical Research

    Boston, Massachusetts, 02131

  • Clinical Research of Brandon, LLC

    Brandon, Florida, 33511

  • Access Research Institute

    Brooksville, Florida, 34613

  • The Ohio State University Department of Psychiatry

    Columbus, Ohio, 43210

  • FutureSearch Trials of Dallas

    Dallas, Texas, 75231

  • InSite Clinical Research

    DeSoto, Texas, 75115

  • Revive Research Institute, Inc

    Elgin, Illinois, 60123

  • Core Clinical Research

    Everett, Washington, 98201

  • North Texas Clinical Trials

    Fort Worth, Texas, 76014

  • CBH Health LLC

    Gaithersburg, Maryland, 20877

  • Collaborative Neuroschience Research, LLC

    Garden Grove, California, 92845

  • Zucker Hillside Hospital

    Glen Oaks, New York, 11004

  • Behavioral Research Specialists, LLC

    Glendale, California, 91206

  • The Medicine Medical Research

    Hollywood, Florida, 33121

  • University of Texas Medical School at Houston

    Houston, Texas, 77054

  • University of Alabama at Birmingham

    Huntsville, Alabama, 35801

  • Sunwise Clinical Research, LLC.

    Lafayette, California, 94549

  • Altea Research Institute, Las Vegas

    Las Vegas, Nevada, 89102

  • Alivation Research, LLC

    Lincoln, Nebraska, 68526

  • Psych Atlanta, PC

    Marietta, Georgia, 30060

  • Hassman Research Institute

    Marlton, New Jersey, 08053

  • Nuovida Research Center

    Miami, Florida, 33145

  • SG Research, LLC

    Miami, Florida, 33145

  • Global Medical Institutes, LLC

    Moosic, Pennsylvania, 18507

  • Aqualane Clinical Research

    Naples, Florida, 34105

  • Excell Research

    Oceanside, California, 92056

  • Clinical Neuroscience Solutions, Inc.

    Orlando, Florida, 32801

  • Alea Research

    Phoenix, Arizona, 85012

  • Global Medical Institutes, LLC

    Princeton, New Jersey, 08510

  • Global Medical Institutes, LLC

    Princeton, New Jersey, 08540

  • Anderson Clinical Reseach

    Redlands, California, 92374

  • Schuster Medical Research Institute

    Sherman Oaks, California, 91403

  • Bio Behavior Health

    Toms River, New Jersey, 08755

  • Collaborative Neuroscience Research, LLC

    Torrance, California, 90502

  • Pacific Clinical Research Management Group

    Upland, California, 91786

  • Ascension Via Christi Research, a division of Ascension Via Christi Hospitals Wichita, Inc.

    Wichita, Kansas, 67214

Other trials in United States

Canada4 sites

  • OCT Research ULC

    Kelowna, British Columbia, V1Y 1Z9

  • AMNDX Inc.

    Markham, Ontario, L3R 1A3

  • St. Michael's Hospital

    Toronto, Ontario, M5B1M4

  • CAMH-Russell Street Site 250 College Street

    Toronto, Ontario, M5T 1R8

Other trials in Canada

About this study

Official title: A Biomarker-Guided, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With Treatment-Resistant Depression

This study was conducted as a randomized, double-blind, placebo-controlled, multi-center Phase 2b study. Approximately 180 subjects with treatment resistant depression who meet all eligibility criteria will be enrolled. The primary endpoint is to demonstrate liafensine is superior to placebo in DGM4 positive patients with TRD.

Read the detailed description

This study is a randomized, double blind, placebo-controlled Phase 2b study to assess the efficacy, safety, tolerability, and pharmacokinetics of liafensine. Eligible patients were randomized 1:1:1 to receive liafensine 1 mg QD, liafensine 2 mg QD, or placebo QD. The main objectives of this study are as follows:

Primary Efficacy Objective: To demonstrate that liafensine was superior to placebo in DGM4 positive patients with TRD as assessed by the change in MADRS total score from baseline to Day 42 of double blind treatment

Key Secondary Efficacy Objective: To evaluate the change from baseline to Day 42 in DGM4 positive patients with TRD treated with liafensine vs placebo on the Clinical Global Impression-Severity Scale (CGI S)

Other Secondary Efficacy Objective: To evaluate the Clinical Global Impression-Improvement Scale (CGI I) at Day 42 in DGM4 positive patients with TRD treated with liafensine vs placebo

Safety Objective: To compare the safety and tolerability of liafensine vs placebo in all randomized patients with TRD who received at least one dose of study drug during double blind treatment

Psychiatric assessments were performed by a psychiatrist or trained and certified clinical staff member. Neurologic assessments were performed by an experienced clinician. Patients who fulfilled Hy's Law, defined as ALT or AST ≥ 3 × ULN and TBL ≥ 2 × ULN, in the absence of significant increase in ALP and in the absence of an alternative diagnosis that explained the increase in total bilirubin, were discontinued, with medical follow up as appropriate.

Being tested
Liafensine, Placebo
Keywords
TRD, Treatment Resistant Depression
Medical subject headings
Depressive Disorder, Treatment-Resistant

What participants receive

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

  • LiafensineDrug

    Also called DB104

    Liafensine

  • PlaceboDrug

    Placebo

Study groups in NCT05113771
Study groupRoleWhat they receive
Liafensine 1mgExperimentalPatients with TRD were treated with liafensine 1 mg QD for 6 weeks.
Receives: Drug: Liafensine
Liafensine 2mgExperimentalPatients with TRD were treated with liafensine 2 mg QD for 6 weeks.
Receives: Drug: Liafensine
PlaceboPlacebo comparatorPatients with TRD were treated with placebo 1 mg QD for 6 weeks.
Receives: Drug: Placebo

What is being measured

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

  1. Change in Montgomery Åsberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 42, in DGM4-positive Patients

    The primary objective of this study was change of Montgomery Åsberg Depression Rating Scale (MADRS) total score (range = 0 60, with higher scores indicating more severe depression) in DGM4 positive patients who were treated with liafensine versus placebo.

    Measured: Baseline to Day 42

Secondary outcomes (2)

  1. Change From Baseline to Day 42 in Clinical Global Impression-Severity Scale (CGI-S) Score in DGM4 Positive Patients

    The secondary endpoint was the change from baseline to Day 42 in Clinical Global Impression-Severity Scale CGI-S score (range = 1-7, with higher scores indicating greater illness) in DGM4 positive patients.

    Measured: Baseline to Day 42

  2. The Clinical Global Impression-Improvement Scale (CGI-I) (Range = 1-7, With Higher Score Indicating Worsening) Was Assessed in DGM4 Positive Patients

    To evaluate the Clinical Global Impression-Improvement Scale (CGI I) (range = 1-7, with higher score indicating worsening) at Day 42 in DGM4 positive patients with TRD treated with liafensine vs placebo

    Measured: 42 days

Timeline

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

  1. First posted9 Nov 2021
  2. Study start29 Jun 2022
  3. Primary completion6 Feb 2024
  4. Study completion5 Mar 2024

Resources

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
Double blind
Who is masked
Participant, Investigator
Enrolment
197 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05113771
Sponsor's protocol ID
DB104-01
Acronym
ENLIGHTEN
Status last verified
Mar 2025
First submitted
29 Oct 2021
Last updated
15 May 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Wang G, Aguado M, Spear MA, Alphs L, Chen C, Huang H, Lu XX, Doostzadeh J, Wu S, Wang S, Patel A, Nemeroff CB, Wang Z, Li A, Luo W. ANK3 as a Novel Genetic Biomarker for Liafensine in Treatment-Resistant Depression: The ENLIGHTEN Randomized Clinical Trial. JAMA Psychiatry. 2025 Dec 1;82(12):1186-1194. doi: 10.1001/jamapsychiatry.2025.2416.

    PubMed 40928787

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Liafensine in people with Treatment Resistant Depression, run by Denovo Biopharma LLC at 45 sites in 2 countries.

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 12 inclusion and 41 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 15 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 45 sites in United States, Canada. 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 15 May 2025). 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 Montgomery Åsberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 42, in DGM4-positive Patients (time frame: Baseline to Day 42). 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 NCT05113771, which also lists 1 linked publication.

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 15 May 2025.

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