A Study of CLE-100 (Oral Esketamine) in Addition to Standard Antidepressant Drug for Major Depressive Disorder - CLEO Study

Recruiting at 46 trial locations

Overseen By Clinical Operations Lead

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Clexio Biosciences Ltd.

Must be taking: Antidepressants

Disqualifiers: Bipolar, Schizophrenia, Substance use, others

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

Compensation: Varies

Number of Visits: Unknown

130 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

No, you will not have to stop taking your current medications. The trial is for people already on stable doses of antidepressant therapy.

What data supports the effectiveness of the drug CLE-100, Oral Esketamine, Placebo, Control, Dummy Treatment?

Research shows that esketamine, when used as a nasal spray, can quickly reduce symptoms of major depressive disorder and suicidal thoughts in patients at risk of suicide, compared to a placebo. ^{1 2 3 4 5}

What safety data exists for esketamine, also known as CLE-100 or Oral Esketamine?

Esketamine has been associated with neurological side effects like sedation, dizziness, and changes in taste. Some studies found that serious and non-serious side effects were not always fully reported, making it hard to assess the complete safety profile. Compared to a placebo, esketamine showed a higher risk of side effects such as nausea and dissociation (feeling disconnected from reality). ^{6 7 8 9 10}

How does intranasal esketamine differ from other drugs for treatment-resistant depression?

Intranasal esketamine is unique because it is administered through the nose, unlike most antidepressants that are taken orally. It works quickly to relieve symptoms of depression, especially in patients who haven't responded to other treatments, and is used alongside traditional antidepressants like SSRIs or SNRIs. ^{2 11 12 13 14}

What is the purpose of this trial?

This trial is testing a new oral medication called esketamine for people with major depression who haven't improved with their current antidepressants. Esketamine works by balancing brain chemicals to help improve mood. The study aims to see if this new treatment is safe and effective. Esketamine is an antidepressant recently approved for treatment-resistant depression, with a novel mechanism of action.

Eligibility Criteria

Inclusion Criteria

Primary diagnosis of MDD, without psychotic features according to DSM-5 and supported by the Mini International Neuropsychiatric Interview (MINI)

Treatment with stable dose of the current antidepressant therapy for at least 4 weeks for the current major depressive episode (MDE)

Body mass index (BMI) between 18 and 40 kg/m2, inclusive

Timeline

Screening

Participants are screened for eligibility to participate in the trial

5 weeks

Treatment (Part A)

Inpatient double-blind treatment phase with CLE-100 or placebo for 1 week

1 week

Inpatient stay

Follow-up (Part A)

Outpatient post-treatment safety follow-up phase after last study drug administration

1 week

Treatment (Part B)

Participants receive CLE-100 or placebo once daily for 4 weeks while continuing their current antidepressant therapy

4 weeks

Follow-up (Part B)

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CLE-100
• Placebo

Participant Groups

Group I: Part B - CLE-100 (oral esketamine) Experimental Treatment 1 Intervention

Part B: 1 oral tablet of CLE-100 once daily for 4 weeks.

Group II: Part A - CLE-100 (oral esketamine) Experimental Treatment 1 Intervention

Part A: 1 oral tablet of CLE-100 once daily for 1 week.

Group III: Part B - Placebo Placebo Group 1 Intervention

Part B: 1 oral tablet of Placebo once daily for 4 weeks.

Group IV: Part A - Placebo Placebo Group 1 Intervention

Part A: 1 oral tablet of Placebo once daily for 1 week.

Who Is Running the Clinical Trial?

Clexio Biosciences Ltd.

Lead Sponsor

Trials

3

Recruited

280+

Findings from Research

In a study of 362 patients with major depressive disorder and active suicidal ideation, those receiving esketamine nasal spray plus standard care showed a significantly higher response rate (63.9% vs 48.0%) compared to those receiving placebo at 4 weeks, indicating its efficacy even for patients who did not respond initially.

Patients who did not show improvement within the first week still had a good chance of achieving response and remission by the end of the 4-week treatment, suggesting that esketamine can be beneficial for those who may not respond quickly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment response to esketamine nasal spray in patients with major depressive disorder and acute suicidal ideation or behavior without evidence of early response: a pooled post hoc analysis of ASPIRE. Turkoz, I., Lopena, O., Salvadore, G., et al.[2022]

In a study of 68 participants at imminent risk for suicide, intranasal esketamine (84 mg) combined with standard treatment led to significantly greater reductions in depression symptoms within 4 hours compared to placebo, with a notable effect size of 0.61.

Esketamine also showed a significant improvement in suicidal thoughts at 4 hours, but the effects diminished by day 25, highlighting the need for ongoing treatment and monitoring for sustained efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Canuso, CM., Singh, JB., Fedgchin, M., 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]

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]

Esketamine has been shown to induce antidepressant effects in patients with Major Depression Disorder (MDD), based on a meta-analysis of four randomized controlled trials involving 551 patients.

However, the analysis revealed a significant increase in adverse effects compared to placebo, including nausea, dissociation, dizziness, and sedation, indicating that while esketamine can be effective, it also carries specific risks that need to be considered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Effects of Esketamine for the Treatment of Major Depression Disorder: Findings from Randomized Controlled Trials. Yang, S., Wang, J., Li, X., et al.[2022]

There is currently no standardized safety monitoring protocol for off-label use of generic ketamine, and safety monitoring for intranasal esketamine varies by jurisdiction, leading to potential gaps in patient safety.

The Ketamine Side Effect Tool (KSET) is recommended as a comprehensive tool for monitoring both acute and long-term side effects of ketamine and esketamine treatments, addressing the lack of agreed frameworks for safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. Bayes, A., Short, B., Zarate, CA., et al.[2023]

In a pilot study involving 14 patients from a larger trial on esketamine nasal spray for treatment-resistant depression, remote raters were able to accurately assess treatment responses, showing a 92.9% predictive value for matching outcomes with site-based assessments.

Esketamine demonstrated efficacy, with 57.1% of patients responding to treatment and 42.9% achieving remission at 2 hours post-dose, despite some experiencing transient dissociative symptoms, highlighting the importance of monitoring TEAEs in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparability of blinded remote and site-based assessments of response to adjunctive esketamine or placebo nasal spray in patients with treatment resistant depression. Targum, SD., Daly, E., Fedgchin, M., et al.[2020]

Intranasal esketamine significantly improves response and remission rates in patients with major depressive disorder (MDD) compared to placebo, with effects starting as early as 2 hours and lasting for at least 28 days, based on a meta-analysis of 4 randomized controlled trials involving 708 patients.

While intranasal esketamine shows rapid antidepressant effects, it is associated with a higher rate of discontinuation due to intolerability, indicating a need for further research on its long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive intranasal esketamine for major depressive disorder: A systematic review of randomized double-blind controlled-placebo studies. Zheng, W., Cai, DB., Xiang, YQ., et al.[2022]

Esketamine hydrochloride (Spravato) is an effective treatment for adults with treatment-resistant major depressive disorder, specifically for those who have not responded to at least two different antidepressants during their current episode.

The treatment involves a nasal spray formulation, starting with a dose of 56 mg for adults under 65 and 28 mg for those 65 and older, with a structured dosing schedule that includes twice-weekly doses for the first month, followed by weekly or biweekly maintenance, and is recommended for at least 6 months after symptom improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Esketamine for treatment-resistant depression. [2021]

References

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

Treatment response to esketamine nasal spray in patients with major depressive disorder and acute suicidal ideation or behavior without evidence of early response: a pooled post hoc analysis of ASPIRE. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study. [2018]

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

Effects of esketamine on patient-reported outcomes in major depressive disorder with active suicidal ideation and intent: a pooled analysis of two randomized phase 3 trials (ASPIRE I and ASPIRE II). [2023]

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

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I). [2020]

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

Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. [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. United States pubmed.ncbi.nlm.nih.gov

Adverse Effects of Esketamine for the Treatment of Major Depression Disorder: Findings from Randomized Controlled Trials. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Comparability of blinded remote and site-based assessments of response to adjunctive esketamine or placebo nasal spray in patients with treatment resistant depression. [2020]

11. Korea (South) pubmed.ncbi.nlm.nih.gov

Long-term Safety and Efficacy of Esketamine Nasal Spray Plus an Oral Antidepressant in Patients with Treatment-resistant Depression- an Asian Sub-group Analysis from the SUSTAIN-2 Study. [2022]

12. Germany pubmed.ncbi.nlm.nih.gov

Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. [2019]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Adjunctive intranasal esketamine for major depressive disorder: A systematic review of randomized double-blind controlled-placebo studies. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Esketamine for treatment-resistant depression. [2021]