Oral Esketamine for Depression

No longer recruiting at 47 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests an oral medication called CLE-100 (esketamine) to determine its effectiveness for individuals with Major Depressive Disorder (MDD) who are already on antidepressants. The research aims to discover if adding CLE-100 can improve symptoms when standard treatments fall short. Participants will receive either CLE-100 or a placebo (a pill with no active drug) to compare results. This trial targets individuals who have experienced MDD without psychotic features for at least 12 weeks and have not responded well to at least two antidepressant treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CLE-100, an oral form of esketamine, has been safe in previous studies. One study found that participants, including those who joined after recovering from the acute phase of COVID-19, tolerated CLE-100 well. Additionally, long-term studies of esketamine used with daily antidepressants did not reveal any new safety issues over periods as long as 4.5 years. However, earlier research noted that esketamine can cause sedation, meaning a feeling of calm or sleepiness, as a common side effect. These findings suggest that CLE-100 is generally safe to use, but monitoring for side effects like sedation is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for MDD?

Most treatments for major depressive disorder, like SSRIs and SNRIs, work by altering the balance of neurotransmitters in the brain. But CLE-100, an oral form of esketamine, works differently by targeting the NMDA receptors, which could lead to faster relief of depressive symptoms. Unlike traditional antidepressants, which can take weeks to show effectiveness, esketamine has the potential to show results in just days. Researchers are excited about this treatment because it offers a new mechanism of action and a promising option for those who haven't found success with other medications.

What evidence suggests that CLE-100 might be an effective treatment for Major Depressive Disorder?

Research has shown that esketamine may help treat major depressive disorder, especially when other treatments have failed. In one study, 47.1% of patients experienced meaningful improvement, with 26.8% showing a strong response and 15.6% reaching remission. Another study found that after 16 weeks of treatment, patients showed more than a 10% improvement in various quality of life measures and a significant drop in depression scores. This trial will evaluate the effectiveness of oral esketamine, specifically CLE-100, which participants may receive. These findings suggest that esketamine, including its oral form like CLE-100, might be effective for people struggling with depression despite trying other treatments. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• CLE-100
• Placebo

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12205164/

Oral esketamine for patients with severe treatment-resistant ... MCID, response, and remission rates were 47.1%, 26.8% and 15.6% respectively. In 45.9% of participants, treatment was continued after 6 weeks to maintain ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40601310/

Esketamine Monotherapy in Adults With Treatment ... The most common treatment-emergent adverse events reported for esketamine (combined doses) were nausea (56 participants [24.8%]), dissociation ( ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2772598724000230

A real-world study examining the impact of esketamine ... After 16-weeks on esketamine, participants showed improvement of greater than 10% across all dimensions of AQoL-8D, HAM-D scores decreased 8.0 points, and ...

4. medrxiv.org medrxiv.org/content/10.1101/2025.09.22.25336317v1.full-text

Efficacy and Safety of Esketamine Nasal Spray in ... Primary efficacy outcomes included change in depressive symptoms, response (≥50% reduction), and remission rates. Secondary outcomes were ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04103892

NCT04103892 | A Study of CLE-100 (Oral Esketamine) in ... Part B will be a study to assess the safety and efficacy of CLE-100 (oral esketamine) in MDD participants currently treated with an antidepressant drug with ...

6. spravatohcp.com spravatohcp.com/mdsi-data-dosing/

MDSI Dosing & Safety Data Limitations of Use: The effectiveness of SPRAVATO® in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10267177/

interim results of the SUSTAIN-3 study No new safety signal was identified during long-term treatment (up to 4.5 years) using intermittent-dosed esketamine in conjunction with daily antidepressant.

8. withpower.com withpower.com/trial/phase-3-disease-8-2019-2f66c

A Study of CLE-100 (Oral Esketamine) in Addition to ... 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 ...

9. clexio.com clexio.com/pipeline/cle-100/

CLE-100 In this study, CLE-100 showed a good safety profile and, in the subgroup of subjects enrolled during the post-acute Covid period, promising efficacy.