A Biomarker-Guided, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With Treatment-Resistant Depression
Overview
- Phase
- Phase 2
- Intervention
- Liafensine
- Conditions
- Treatment Resistant Depression
- Sponsor
- Denovo Biopharma LLC
- Enrollment
- 197
- Locations
- 43
- Primary Endpoint
- Change in Montgomery Åsberg Depression Rating Scale (MADRS) Total Score From Baseline to Day 42, in DGM4-positive Patients
- Status
- Completed
- Last Updated
- 11 months ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
- •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.
Exclusion Criteria
- •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.
- •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:
Arms & Interventions
Liafensine 1mg
Patients with TRD were treated with liafensine 1 mg QD for 6 weeks.
Intervention: Liafensine
Liafensine 2mg
Patients with TRD were treated with liafensine 2 mg QD for 6 weeks.
Intervention: Liafensine
Placebo
Patients with TRD were treated with placebo 1 mg QD for 6 weeks.
Intervention: Placebo
Outcomes
Primary Outcomes
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
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.
Secondary Outcomes
- Change From Baseline to Day 42 in Clinical Global Impression-Severity Scale (CGI-S) Score in DGM4 Positive Patients(Baseline to Day 42)
- The Clinical Global Impression-Improvement Scale (CGI-I) (Range = 1-7, With Higher Score Indicating Worsening) Was Assessed in DGM4 Positive Patients(42 days)