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Azetukalner versus placebo for major depressive disorder (X‑NOVA3)

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

Phase 3 Interventional Xenon Pharmaceuticals Inc. · NCT07076407

This study will see if taking azetukalner alone helps adults with major depressive disorder feel better than a placebo.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment450 (estimated)
Ages18 Years to 74 Years
SexAll
SponsorXenon Pharmaceuticals Inc. Industry-sponsored
Locations42 sites (Dothan, Alabama and 41 other locations)
Trial IDNCT07076407 on ClinicalTrials.gov

What this trial studies

X‑NOVA3 is a Phase 3, multicenter, randomized, double‑blind, placebo‑controlled trial testing azetukalner as a monotherapy in adults with current major depressive disorder. Eligible participants are aged 18–74, had their first depressive episode before age 50, and have a current episode lasting 6 weeks to 24 months, with diagnosis confirmed by the MINI per DSM‑5‑TR criteria. Participants will be randomized to receive azetukalner or matched placebo and will be monitored for changes in depressive symptoms, safety, and tolerability using standardized outcome measures and adverse event reporting. The study is conducted at several U.S. clinical centers including University of Alabama at Birmingham and regional research clinics in Alabama and Arkansas.

Who should consider this trial

Good fit: Adults 18–74 with a DSM‑5‑TR confirmed current major depressive episode (first episode before age 50), episode duration of 6 weeks to 24 months, and BMI ≤40 kg/m2 who do not have excluded psychiatric diagnoses are ideal candidates.

Not a fit: People with bipolar disorder, primary psychotic disorders, obsessive‑compulsive disorder, MDD with psychotic/catatonic/mixed features, seasonal or peripartum/perimenopausal onset, or other excluded conditions are unlikely to benefit from this monotherapy protocol.

Why it matters

Potential benefit: If effective, azetukalner could provide a new single‑agent antidepressant option that reduces depressive symptoms for adults with MDD.

How similar studies have performed: Earlier‑phase studies of azetukalner (XEN1101) reported preliminary signals of efficacy and acceptable tolerability, and this Phase 3 trial builds on those earlier findings.

Eligibility criteria

Show full inclusion / exclusion criteria 
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.

Where this trial is running

Dothan, Alabama and 41 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Major Depressive DisorderDepressionAntidepressantXEN1101Azetukalner
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.