Clinical trial NCT05113771: A Biomarker-Guided, Randomized, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With TRD
Official title: A Biomarker-Guided, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With Treatment-Resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Treatment Resistant Depression
Keywords: TRD, Treatment Resistant Depression
Lead sponsor: Denovo Biopharma LLC
Sponsor class: INDUSTRY
First posted: 2021-11-09
Enrollment: 197
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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. The primary endpoint is to demonstrate liafensine is superior to placebo in DGM4 positive patients with TRD.

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.

Eligibility criteria: Inclusion Criteria:

1. Provide signed informed consent which includes pharmacogenomic (PGx) testing.
2. 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).
3. 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.
4. 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.
5. Pregnancy conception limitations

   * 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.
6. Be fluent in the local language.
7. Male or female aged 18 to 70, inclusive, at time of enrollment.
8. Have a HAMD-17 total score ≥ 21 at screening.
9. 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.

Exclusion Criteria:

1. Prior participation in a study with liafensine
2. Used any investigational drug product, device, or biologic within 6 months or five half-lives (whichever is longer) prior to baseline (Day -1).
3. A positive pregnancy test result or currently breastfeeding.
4. 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.
5. 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.
6. 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.
7. Uncontrolled human immunodeficiency virus (HIV) infection according to local guidance.
8. Uncontrolled abnormal thyroid function according to local guidance.
9. 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.
10. 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).
11. 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.
12. 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.
13. 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
14. History of seizure, other than childhood febrile seizures.
15. 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.
16. History of clinically significant symptomatic orthostatic hypotension (ie, postural syncope).
17. History of narrow angle glaucoma.
18. 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.
19. 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).
20. 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).
21. 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.
22. Use of potent inducers of CYP3A4 (eg, rifampin, rifabutin, phenytoin, carbamazepine, or phenobarbital) within 2 weeks prior to baseline (Day-1).
23. Current diagnosis or history of a psychotic disorder, MDD with psychotic features, manic or hypomanic episode of bipolar or related disorders.
24. 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.
25. Hospitalized or discharged from psychiatric ward within 8 weeks prior to the screening visit and planned hospitalization for any condition(s) during the study.
26. 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.
27. Significant risk of suicide determined by:

    1. 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
    2. History of suicidal behavior as indicated by a "yes" response on the Suicidal Behavior section of the C-SSRS ("In the past year") or
    3. A score ≥ 5 on Item 10 (suicidal thoughts) of the MADRS at screening or baseline (Day -1); or
    4. Has attempted suicide within 6 months prior to the initial screening visit.
28. Previous allogenic bone marrow transplant.
29. Received non-leukocyte-depleted whole blood transfusion within 4 months prior to PGx testing at Screening.
30. 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.

Primary outcomes:
measure: Change in Montgomery Åsberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 42, in DGM4-positive Patients
timeFrame: Baseline to Day 42
Secondary outcomes:
measure: Change From Baseline to Day 42 in Clinical Global Impression-Severity Scale (CGI-S) Score in DGM4 Positive Patients
timeFrame: Baseline to Day 42
measure: The Clinical Global Impression-Improvement Scale (CGI-I) (Range = 1-7, With Higher Score Indicating Worsening) Was Assessed in DGM4 Positive Patients
timeFrame: 42 days
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Alea Research
state: Arizona
city: Garden Grove
country: United States
facility: Collaborative Neuroschience Research, LLC
state: California
city: Glendale
country: United States
facility: Behavioral Research Specialists, LLC
state: California
city: Lafayette
country: United States
facility: Sunwise Clinical Research, LLC.
state: California
city: Oceanside
country: United States
facility: Excell Research
state: California
city: Redlands
country: United States
facility: Anderson Clinical Reseach
state: California
city: Sherman Oaks
country: United States
facility: Schuster Medical Research Institute
state: California
city: Torrance
country: United States
facility: Collaborative Neuroscience Research, LLC
state: California
city: Upland
country: United States
facility: Pacific Clinical Research Management Group
state: California
city: Brandon
country: United States
facility: Clinical Research of Brandon, LLC
state: Florida
city: Brooksville
country: United States
facility: Access Research Institute
state: Florida
city: Hollywood
country: United States
facility: The Medicine Medical Research
state: Florida
city: Miami
country: United States
facility: Nuovida Research Center
state: Florida
city: Miami
country: United States
facility: SG Research, LLC
state: Florida
city: Naples
country: United States
facility: Aqualane Clinical Research
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions, Inc.
state: Florida
city: Atlanta
country: United States
facility: CenExel Atlanta Center for Medical Research
state: Georgia
city: Marietta
country: United States
facility: Psych Atlanta, PC
state: Georgia
city: Elgin
country: United States
facility: Revive Research Institute, Inc
state: Illinois
city: Wichita
country: United States
facility: Ascension Via Christi Research, a division of Ascension Via Christi Hospitals Wichita, Inc.
state: Kansas
city: Baltimore
country: United States
facility: Pharmasite Research, Inc.
state: Maryland
city: Gaithersburg
country: United States
facility: CBH Health LLC
state: Maryland
city: Boston
country: United States
facility: Boston Clinical Trials & Medical Research
state: Massachusetts
city: Bloomfield
country: United States
facility: Neurobehavioral Medicine Group
state: Michigan
city: Lincoln
country: United States
facility: Alivation Research, LLC
state: Nebraska
city: Las Vegas
country: United States
facility: Altea Research Institute, Las Vegas
state: Nevada
city: Marlton
country: United States
facility: Hassman Research Institute
state: New Jersey
city: Princeton
country: United States
facility: Global Medical Institutes, LLC
state: New Jersey
city: Princeton
country: United States
facility: Global Medical Institutes, LLC
state: New Jersey
city: Toms River
country: United States
facility: Bio Behavior Health
state: New Jersey
city: Albuquerque
country: United States
facility: IMA Clinical Research
state: New Mexico
city: Glen Oaks
country: United States
facility: Zucker Hillside Hospital
state: New York
city: Columbus
country: United States
facility: The Ohio State University Department of Psychiatry
state: Ohio
city: Allentown
country: United States
facility: Lehigh Center for Clinical Research, LLC
state: Pennsylvania
city: Moosic
country: United States
facility: Global Medical Institutes, LLC
state: Pennsylvania
city: Dallas
country: United States
facility: FutureSearch Trials of Dallas
state: Texas
city: DeSoto
country: United States
facility: InSite Clinical Research
state: Texas
city: Fort Worth
country: United States
facility: North Texas Clinical Trials
state: Texas
city: Houston
country: United States
facility: University of Texas Medical School at Houston
state: Texas
city: Everett
country: United States
facility: Core Clinical Research
state: Washington
city: Kelowna
country: Canada
facility: OCT Research ULC
state: British Columbia
city: Markham
country: Canada
facility: AMNDX Inc.
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: CAMH-Russell Street Site 250 College Street
state: Ontario
Study officials:
affiliation: Denovo Biopharma
name: Matthew A Spear, M.D.
role: STUDY_DIRECTOR
References: