Azetukalner for Depression

(X-NOVA2 Trial)

Recruiting at2 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Verified Trial

Recruiting

Sponsor: Xenon Pharmaceuticals Inc.

Must not be taking: Antidepressants, Benzodiazepines

Disqualifiers: Bipolar, Schizophrenia, Substance use, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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)

Will I have to stop taking my current medications?

Yes, you will need to stop taking antidepressants and certain other medications like benzodiazepines at least 2 weeks before starting the trial (4 weeks for fluoxetine).

What data supports the effectiveness of the drug Azetukalner for depression?

While there is no direct data on Azetukalner, studies show that adding aripiprazole to existing antidepressant treatments can help patients who haven't responded well to other medications. This suggests that similar strategies might be effective for treatment-resistant depression. ^{1 2 3 4 5}

What safety data exists for Azetukalner (Esketamine) in humans?

Esketamine, used for treatment-resistant depression, has been associated with neurological side effects like sedation and dizziness. Safety reporting in clinical trials has been poor, with many adverse events not fully documented in published articles. ^{6 7 8 9 10}

Research Team

Eligibility Criteria

Adults aged 18-74 with Major Depressive Disorder (MDD) as per DSM-5, currently in a depressive episode lasting 6 weeks to 24 months. Participants must have had their first MDE before age 50 and have a BMI of ≤40 kg/m2. Excluded are those with other mood disorders, recent substance abuse, certain psychiatric conditions like bipolar or schizophrenia, active suicidal intent, non-suicidal self-harm within the past year, pregnancy, or recent antidepressant use.

Inclusion Criteria

Have you felt at least 3 of the following things recently? Feeling sad; low energy or feeling tired; hopelessness or putting yourself down; not being interested in things that you usually enjoy such as hobbies or activities, or friends and family; difficulty concentrating or focusing on things; appetite changes like pushing yourself to eat or overeating; difficulty falling or staying asleep, or oversleeping?

Exclusion Criteria

Have you tried 3 or more antidepressants that haven't worked?

Have you been diagnosed with Bipolar Disorder?

Have you been diagnosed with Obsessive-Compulsive Disorder?

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azetukalner 20 mg or placebo as a monotherapy for Major Depressive Disorder

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Azetukalner (Other)

Trial Overview The X-NOVA2 study is testing Azetukalner against a placebo in adults with MDD. This Phase 3 trial is double-blind and placebo-controlled to ensure neither researchers nor participants know who receives the actual medication versus the placebo for unbiased results.

Participant Groups

Group I: Azetukalner Experimental Treatment 1 Intervention

Azetukalner 20 mg

Group II: Placebo Placebo Group 1 Intervention

Placebo

Who Is Running the Clinical Trial?

Xenon Pharmaceuticals Inc.

Lead Sponsor

Trials

19

Recruited

3,400+

Findings from Research

Most patients with treatment-resistant depression can respond positively to a well-chosen new medication or a correctly administered previous treatment, suggesting that careful selection is key to improving outcomes.

The use of drug combinations is less common than often practiced, and treatment decisions should be based more on clinical evidence and patient education rather than solely on experience, emphasizing the importance of hope and understanding in the treatment process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of treatment-resistant unipolar and chronically depressed patients. Reus, VI.[2019]

In a systematic review of 16 randomized clinical trials involving 1700 outpatients, antidepressant medication (ADM) showed a significant advantage over cognitive behavioral therapy (CBT) in reducing depression symptoms as measured by the Hamilton Rating Scale for Depression (HAM-D).

Baseline depression severity did not significantly influence the effectiveness of either CBT or ADM in terms of symptom reduction, response, or remission rates, suggesting that both treatments can be effective regardless of initial severity of depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Depression Severity as Moderator of Depression Outcomes Between Cognitive Behavioral Therapy vs Pharmacotherapy: An Individual Patient Data Meta-analysis. Weitz, ES., Hollon, SD., Twisk, J., et al.[2018]

A survey of 175 psychiatrists in the UK revealed that many prefer increasing doses of tricyclic medications or switching SSRIs for treating refractory depression, rather than using more effective options like lithium or T3 augmentation.

39% of psychiatrists expressed a lack of confidence in managing refractory depression, highlighting a need for improved training and continuing professional development in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological choices after one antidepressant fails: a survey of UK psychiatrists. Shergill, SS., Katona, CL.[2022]

In a 12-week study involving 15 patients with treatment-resistant unipolar depression, 50% of participants responded positively to aripiprazole as an adjunctive treatment, showing at least a 50% reduction in depression severity.

Despite some side effects leading to a 26.7% dropout rate, the results support aripiprazole's effectiveness in enhancing the treatment of major depression that hasn't improved with standard SSRIs or SNRIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aripiprazole as an adjunctive treatment for refractory unipolar depression. Hellerstein, DJ., Batchelder, S., Hyler, S., et al.[2015]

In a study of 13 patients with major depression who did not respond adequately to antidepressants, adding aripiprazole for 8 weeks led to significant reductions in depression scores, with 63.6% of patients showing at least a 50% improvement.

The treatment was well-tolerated, with no serious side effects reported, suggesting that aripiprazole could be a beneficial augmentation strategy for patients struggling with inadequate responses to standard antidepressant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aripiprazole augmentation for treatment of patients with inadequate antidepressants response. Pae, CU., Patkar, AA., Jun, TY., et al.[2022]

A study analyzing 720 cases of esketamine-related neurological adverse events (AEs) from 2019 to 2021 identified 21 safety signals, with sedation being the most concerning (ROR of 204.00), indicating potential long-term safety issues with esketamine.

The severity of neurological AEs was influenced by factors such as esketamine dosage and co-prescription with other medications, highlighting the need for careful monitoring and management of these risks in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological Adverse Events Associated With Esketamine: A Disproportionality Analysis for Signal Detection Leveraging the FDA Adverse Event Reporting System. Guo, H., Wang, B., Yuan, S., et al.[2022]

In 2006, several drugs were associated with significant safety concerns, including cardiovascular events linked to erythropoietins and macular edema associated with rosiglitazone, highlighting the need for careful monitoring by prescribers.

Other notable adverse reactions included serious complications from aprotinin, long-term use of linezolid, and congenital anomalies linked to paroxetine and lamotrigine, emphasizing the importance of understanding the safety profiles of medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance and teratovigilance]. Livio, F., Buclin, T., Biollaz, J.[2013]

Ketamine and esketamine demonstrate rapid antidepressant effects, with improvements in clinical response observed within 40 minutes to 1 week for ketamine and 2 hours to 4 weeks for esketamine, along with reductions in depression scores and suicidality.

Despite their effectiveness, the long-term safety and efficacy of ketamine and esketamine remain uncertain, and the overall quality of the studies reviewed was critically low, highlighting the need for more rigorous research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. Lima, TM., Visacri, MB., Aguiar, PM.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Management of treatment-resistant unipolar and chronically depressed patients. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Baseline Depression Severity as Moderator of Depression Outcomes Between Cognitive Behavioral Therapy vs Pharmacotherapy: An Individual Patient Data Meta-analysis. [2018]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacological choices after one antidepressant fails: a survey of UK psychiatrists. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Aripiprazole as an adjunctive treatment for refractory unipolar depression. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Aripiprazole augmentation for treatment of patients with inadequate antidepressants response. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Neurological Adverse Events Associated With Esketamine: A Disproportionality Analysis for Signal Detection Leveraging the FDA Adverse Event Reporting System. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Reporting of harms in clinical trials of esketamine in depression: a systematic review. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance and teratovigilance]. [2013]

9. Ireland pubmed.ncbi.nlm.nih.gov

Self-reported review of the value of esketamine in patients with treatment-resistant depression: Understanding the patient experience in the STRIVE Study. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]