Azetukalner for Depression

(X-NOVA-OLE Trial)

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Xenon Pharmaceuticals Inc.

Disqualifiers: Pregnancy, Suicidal risk, Protocol deviations, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

460 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. However, since the study is evaluating azetukalner as a monotherapy (treatment using only one drug), it might be likely that you will need to stop other medications. Please consult with the study team for specific guidance.

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. Patients in a study reported satisfaction with esketamine treatment, but adverse events were consistent with known safety concerns. ^{1 2 3 4 5}

What is the purpose of this trial?

X-NOVA-OLE is a multicenter, open-label study to evaluate the long-term safety, tolerability, and efficacy of azetukalner as a monotherapy in adult participants who successfully completed an antecedent Phase 3 study of azetukalner in Major Depressive Disorder (MDD).

Eligibility Criteria

This trial is for adults who have Major Depressive Disorder and were part of a previous Phase 3 study of Azetukalner. It's not specified who can't join, but typically people with certain health issues or taking conflicting medications might be excluded.

Inclusion Criteria

Participant successfully completed the treatment period of an antecedent azetukalner Phase 3 study in MDD

Participant is willing to comply with the contraception requirements

I understand and agree to the study's requirements.

Exclusion Criteria

Participant had any protocol deviations in an antecedent azetukalner study that, in the opinion of the investigator, would preclude participation in this study

Participant met any of the withdrawal criteria, or discontinued study drug early, or was terminated early from an antecedent study

Participant is unable to comply with study procedures or is inappropriate for the study, as judged by the investigator

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azetukalner as a monotherapy for long-term evaluation of safety, tolerability, and efficacy

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants continue to receive azetukalner for long-term evaluation

Treatment Details

Interventions

• Azetukalner

Trial Overview The focus is on Azetukalner as a solo treatment for depression. Participants from an earlier study will continue to use this medication to see how safe it is over time and if it keeps working well.

Participant Groups

Group I: Azetukalner 20 mg Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Xenon Pharmaceuticals Inc.

Lead Sponsor

Trials

19

Recruited

3,400+

Findings from Research

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]

A review of 10 clinical trials on esketamine for resistant depression found that 90% of the trials had low-quality reporting of adverse events (AEs), indicating significant gaps in safety data.

The study revealed that 41.5% of serious AEs and 39% of non-serious AEs were not reported in published articles, particularly psychiatric and cardiovascular events, suggesting that the assessment of esketamine's risk-benefit balance may be inaccurate due to incomplete harm reporting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reporting of harms in clinical trials of esketamine in depression: a systematic review. Taillefer de Laportalière, T., Jullien, A., Yrondi, A., et al.[2023]

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]

In a study of 23 adults with treatment-resistant depression, 91.8% reported significant improvements in emotional and daily functioning after using esketamine nasal spray (ESK) alongside an oral antidepressant (OAD).

Patients noted key benefits of ESK treatment, including its effectiveness, rapid onset of action, and a side-effect profile consistent with existing safety data, leading to high satisfaction rates (100% reported satisfaction).

NCBI (Pubmed)

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. Starr, HL., Abell, J., Larish, A., et al.[2021]

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. 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]

2. England pubmed.ncbi.nlm.nih.gov

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

3. Switzerland pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance and teratovigilance]. [2013]

4. 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]

5. Germany pubmed.ncbi.nlm.nih.gov

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