A Randomized Study of Azetukalner Versus Placebo in Major Depressive Disorder (X-NOVA2)

A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study to Evaluate Azetukalner in Moderate-to-Severe Major Depressive Disorder

X-NOVA2 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the clinical efficacy, safety, and tolerability of azetukalner as a monotherapy in adult participants diagnosed with Major Depressive Disorder (MDD)

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Azetukalner; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 450
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Xenon Medical Affairs; Phone Number: 1-604-484-3300; Email: XenonCares@xenon-pharma.com

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Recruiting
      • IMA Clinical Research Phoenix
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Recruiting
      • Woodland International Research Group
    • Rogers, Arkansas, United States, 72758
      • Recruiting
      • Woodland Research Northwest
  • California
    • Glendale, California, United States, 91206
      • Recruiting
      • Behavioral Research Specialists, LLC
    • Huntington Beach, California, United States, 92647
      • Recruiting
      • Marvel Clinical Research
    • Irvine, California, United States, 92614
      • Recruiting
      • Irvine Clinical Research
    • Los Angeles, California, United States, 90025
      • Recruiting
      • Calneuro Research Group, Inc.
    • Oceanside, California, United States, 92056
      • Recruiting
      • Excell Research Inc.
    • Orange, California, United States, 92868
      • Recruiting
      • NRC Research Institute
    • Orange, California, United States, 92866
      • Recruiting
      • ATP Clinical Research
    • Torrance, California, United States, 90504
      • Recruiting
      • CenExel CNS-TO (Collaborative Neuroscience Research)
    • Walnut Creek, California, United States, 94596
      • Recruiting
      • Sunwise Clinical Research
  • Connecticut
    • Cromwell, Connecticut, United States, 06416
      • Recruiting
      • Ct Clinical Research Associates
  • Florida
    • Coral Springs, Florida, United States, 33067
      • Recruiting
      • CNS Clinical Research Group
    • Hialeah, Florida, United States, 33016
      • Recruiting
      • Neoclinical Research
    • Jacksonville, Florida, United States, 32256
      • Recruiting
      • Clinical Neuroscience Solutions, Inc.
    • Lakeland, Florida, United States, 33803
      • Recruiting
      • Accel Research Sites Lakeland
    • Largo, Florida, United States, 33777
      • Recruiting
      • Accel Research Sites - St. Petersburg-Largo
    • Miami, Florida, United States, 33165
      • Recruiting
      • Pharmasouth Research
    • Miami Beach, Florida, United States, 33140
      • Terminated
      • Quantum Clinical Trials
    • North Miami Beach, Florida, United States, 33162
      • Recruiting
      • Harmony Clinical Research Inc
    • Orlando, Florida, United States, 32801
      • Recruiting
      • Clinical Neuroscience Solutions, Inc.
    • Orlando, Florida, United States, 32807
      • Recruiting
      • Combined Research Orlando Phase I-IV
    • Pensacola, Florida, United States, 32503
      • Recruiting
      • Panhandle Research and Medical Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Recruiting
      • Advanced Discovery Research
    • Atlanta, Georgia, United States, 30328
      • Recruiting
      • Synexus - Atlanta
    • Decatur, Georgia, United States, 30030
      • Recruiting
      • CenExel iResearch
    • Marietta, Georgia, United States, 30060
      • Recruiting
      • Psych Atlanta, Pc
    • Savannah, Georgia, United States, 31405
      • Recruiting
      • Cenexel Iresearch - Savannah
  • Idaho
    • Boise, Idaho, United States, 83704
      • Recruiting
      • Northwest Clinical Trials Inc
  • Illinois
    • Chicago, Illinois, United States, 60634
      • Recruiting
      • Chicago Research Center Inc.
  • Massachusetts
    • Boston, Massachusetts, United States, 02131
      • Recruiting
      • Boston Clinical Trials Llc
    • Springfield, Massachusetts, United States, 01103
      • Recruiting
      • ELIXIA
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • Recruiting
      • IMA Clinical Research Las Vegas
    • Las Vegas, Nevada, United States, 89119
      • Recruiting
      • Redbird Research
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Recruiting
      • IMA Clinical Research
  • New York
    • Brooklyn, New York, United States, 11229
      • Recruiting
      • Integrative Clinical Trials
    • Staten Island, New York, United States, 10314
      • Recruiting
      • Richmond Behavioral Associates
  • North Carolina
    • Charlotte, North Carolina, United States, 28211
      • Recruiting
      • New Hope Clinical Research
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Recruiting
      • Pahl Pharmaceutical Professionals Llc
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Recruiting
      • Lehigh Center for Clinical Research
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Recruiting
      • Clinical Neuroscience Solutions, Inc.
  • Texas
    • Plano, Texas, United States, 75093
      • Recruiting
      • AIM Trials, LLC
    • Plano, Texas, United States, 75024
      • Recruiting
      • Delricht Research - Plano
    • Wichita Falls, Texas, United States, 76309
      • Recruiting
      • Grayline Research Center
  • Washington
    • Everett, Washington, United States, 98201
      • Recruiting
      • Core Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Adults ≥18 and ≤74 years of age and experienced their first major depressive episode (MDE) prior to 50 years of age
• Body Mass Index (BMI) ≤40 kg/m2
• Meets the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revised (DSM-5-TR) criteria for current major depressive disorder and is currently in an MDE, confirmed using the Mini International Neuropsychiatric Interview (MINI)
• Participant's current MDE has a duration of ≥6 weeks and ≤24 months.

Key Exclusion Criteria:

• Participant has a primary diagnosis of a mood disorder other than MDD.
• Participant has a history of any of the following: MDD with psychotic or catatonic features; MDD with mixed features; Bipolar I or II disorder; Obsessive-compulsive disorder; Schizophrenia, primary thought disorder, or other psychotic disorder.
• Participant has a current diagnosis of any of the following: MDD with seasonal pattern; Depression with peripartum or perimenopausal onset; Post traumatic stress disorder; Antisocial or borderline personality disorder (or presence of clinically significant borderline personality traits); Panic disorder and/or agoraphobia; ADHD treated with a psychostimulant, diagnosed during the current MDE, or with unstable symptoms, as judged by the investigator.
• Participant has a substance (excluding tobacco) or alcohol use disorder within the 12 months prior to screening.
• Participant has had an active suicidal plan/intent within the 6 months prior to screening, presence of suicidal behavior in the last 2 years, or >1 suicide attempt >24 years of age.
• Participant has a history of non-suicidal self-harm behavior in the 12 months prior to screening.
• Participant has used antidepressants or other prohibited medications (including benzodiazepines), within the 2 weeks (4 weeks for fluoxetine) or within a period less than 5 times the drug's half-life, whichever is longer, prior to randomization.
• Participant has a history of non-response to ≥2 antidepressant drugs of adequate dose and duration in the current MDE as determined by the Antidepressant Treatment Response Questionnaire (ATRQ).
• Participants with medical conditions that may interfere with the purpose or conduct of the study
• Participant is pregnant, breastfeeding, or planning to become pregnant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo taken orally once a day with food (with the evening meal when possible) for 6 weeks
Experimental: Azetukalner; Azetukalner 20 mg	Drug: Azetukalner; Azetukalner 20 mg taken orally once a day with food (with the evening meal when possible) for 6 weeks; Other Names: XEN1101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in the Hamilton Depression Rating Scale, 17-item (HAMD-17) score at Week 6	The HAMD-17 consists of 17 items that are used to rate the severity of depression symptoms. Each item is scored in a range of 0 to 2 points or 0 to 4 points, with higher scores indicating a greater degree of depression. The score for each item is summed to compute a total score, which ranges from 0 to 52 points.	Baseline to Week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in the Snaith-Hamilton Pleasure Scale (SHAPS) score at Week 6	The SHAPS is a 14-item self-report questionnaire used to assess anhedonia. Each item on the SHAPS is worded so that higher scores indicate greater anhedonia. A total score can be derived by summing the responses to each item. Items answered with "strongly agree" are assigned a score of 1, while "strongly disagree" responses are assigned a score of 4 points. Total scores on the SHAPS can range from 14 to 56 points, with higher scores corresponding to higher levels of anhedonia.	Baseline to Week 6
Change from baseline in the Hamilton Depression Rating Scale, 17-item (HAMD-17) score at Week 1	The HAMD-17 consists of 17 items that are used to rate the severity of depression symptoms. Each item is scored in a range of 0 to 2 points or 0 to 4 points, with higher scores indicating a greater degree of depression. The score for each item is summed to compute a total score, which ranges from 0 to 52 points.	Baseline to Week 1
Change from baseline in the Clinical Global Impression of Severity (CGI-S) score at Week 6	The CGI-S is a clinician-rated global measure of participant overall disease severity. Participants are rated on a 7-point severity scale, with higher scores indicating more severe depression.	Baseline to Week 6
To assess the safety and tolerability of azetukalner (e.g., adverse events)		From screening (approximately 4 weeks prior to baseline) through to 8 weeks post-final dose.

Collaborators and Investigators

• Sponsor: Xenon Pharmaceuticals Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: January 9, 2025
• First Submitted That Met QC Criteria: January 9, 2025
• First Posted (Actual): January 15, 2025

Study Record Updates

• Last Update Posted (Estimated): October 22, 2025
• Last Update Submitted That Met QC Criteria: October 20, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Depression; Antidepressant; XEN1101; Azetukalner
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major; XEN1101
• Other Study ID Numbers: XPF-010-D301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No