ALTO-203 for Depression

Recruiting at14 trial locations

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Alto Neuroscience

Must not be taking: Antidepressants

Disqualifiers: Unstable medical condition, Bipolar, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to determine the pharmacodynamic effects of ALTO-203 in patients with MDD in a randomized, placebo-controlled, single-dose crossover treatment period. Additionally, safety, tolerability, and PK will be assessed in a subsequent randomized placebo-controlled multi-dose parallel-group treatment period of 28 days. Participants will complete subjective response questionnaires and perform cognitive tasks during the single-dose period, in which participants will receive ALTO-203 25 μg and 75 μg, as well as placebo. During the multiple-dose period, participants will receive either ALTO-203 25 μg, 75 μg , or placebo. Safety will be assessed over the single dose and 28-day multiple dose periods.

Will I have to stop taking my current medications?

The trial requires that participants are not taking antidepressants at the second screening visit, and some medications may be prohibited. It's best to discuss your current medications with the trial team to see if they are allowed.

What data supports the effectiveness of the drug ALTO-203 for depression?

The research on nefazodone, a similar antidepressant, shows it is effective in treating major depression, including severe and recurrent cases, with significant improvements in depression rating scales. This suggests that ALTO-203, if similar, might also be effective for depression. ^{1 2 3 4 5}

Is ALTO-203 (esketamine) safe for humans?

Esketamine, used for depression, has shown no unexpected safety concerns in studies, but common side effects include dissociation (feeling disconnected), vertigo (dizziness), and dizziness. Some reports indicate poor quality in adverse event reporting, and there are concerns about neurological side effects, so careful monitoring is advised. ^{6 7 8 9 10}

Research Team

Eligibility Criteria

This trial is for individuals with Major Depressive Disorder (MDD), particularly those experiencing anhedonia and depression. Participants will be involved in a study assessing the effects of a new treatment over single and multiple doses.

Inclusion Criteria

I experience a lack of pleasure in activities I once enjoyed.

Willing to comply with all study assessments and procedures

I have been diagnosed with moderate depression.

Exclusion Criteria

I have a health condition that is not stable.

Diagnosed bipolar disorder, psychotic disorder, or dementia

I am not taking any medications that are not allowed in the study.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Single-Dose Treatment

Participants receive single doses of ALTO-203 25 μg, 75 μg, and placebo to evaluate pharmacodynamic measures

1 day

Pre-Dose, 1.5 hours, 3 hours, and 5 hours on Day 1

Multi-Dose Treatment

Participants receive daily doses of ALTO-203 25 μg, 75 μg, or placebo for 28 days to assess safety, tolerability, and PK

28 days

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ALTO-203 (Other)

Trial Overview The trial is testing ALTO-203 at two different strengths, 25 μg and 75 μg, against a placebo. It aims to understand how the drug works (pharmacodynamics), its safety, tolerability, and movement through the body (pharmacokinetics) over both single-dose and multi-dose periods.

Participant Groups

Group I: ALTO-203 75 μg Experimental Treatment 1 Intervention

Drug: ALTO-203 75 μg Single-Dose Treatment Period: Single Dose, ALTO-203 75 μg Multi-Dose Treatment Period: ALTO-203 75 μg, administered orally, once daily for 28 days

Group II: ALTO-203 25 μg Experimental Treatment 1 Intervention

Drug: ALTO-203 25 μg Single-Dose Treatment Period: Single Dose, ALTO-203 25 μg Multi-Dose Treatment Period: ALTO-203 25 μg, administered orally, once daily for 28 days

Group III: Placebo Placebo Group 1 Intervention

Drug: Placebo Single-Dose Treatment Period: Single Dose, Placebo Multi-Dose Treatment Period: Placebo, administered orally, once daily for 28 days

Who Is Running the Clinical Trial?

Alto Neuroscience

Lead Sponsor

Trials

11

Recruited

1,300+

Findings from Research

In two large trials involving adults with major depressive disorder who did not respond adequately to standard antidepressants, adjunctive treatment with aripiprazole (2-20 mg/day) significantly improved depression scores compared to placebo, starting from 1-2 weeks into treatment.

Aripiprazole was generally well tolerated, with most side effects being mild to moderate, and it also led to higher rates of response and remission compared to placebo, indicating its efficacy as an adjunctive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aripiprazole: in major depressive disorder. Weber, J., Lyseng-Williamson, KA., Scott, LJ.[2021]

In a double-blind trial involving 90 patients with moderate to severe major depressive episodes, Org 3770 demonstrated significant efficacy compared to placebo, particularly in the first four weeks and at the end of the six-week treatment period.

Org 3770 was well-tolerated, with only minor side effects such as somnolence and increased appetite, indicating it is a safe option for treating major depressive disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled study of Org 3770 in depressed outpatients. Claghorn, JL., Lesem, MD.[2019]

Nefazodone, an antidepressant, was effective in treating patients with moderate to severe depression, including those with melancholic features and recurrent episodes, based on a pooled analysis of four placebo-controlled studies involving 664 participants.

The studies showed that nefazodone improved depression symptoms significantly, as measured by the Hamilton Rating Scale for Depression and the Clinical Global Impressions scale, indicating its efficacy across clinically important subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nefazodone in the treatment of severe, melancholic, and recurrent depression. Marcus, RN., Mendels, J.[2018]

Nefazodone was found to be an effective treatment for major depression in Spanish-monolingual Hispanics, with a 63% response rate that aligns with previous studies on non-Hispanic subjects.

Despite similar efficacy and adverse effect rates to prior trials, a notably high dropout rate of 42% among participants suggests that factors beyond side effects may influence treatment adherence in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open trial of nefazodone among Hispanics with major depression: efficacy, tolerability, and adherence issues. Sánchez-Lacay, JA., Lewis-Fernández, R., Goetz, D., et al.[2021]

Esketamine nasal spray combined with a newly initiated oral antidepressant showed significant efficacy in treating treatment-resistant depression, with a number needed to treat (NNT) of 8 for response and 6 for remission after 4 weeks, indicating a strong potential benefit.

While there are some adverse effects associated with esketamine, such as dissociation and nausea, the likelihood to be helped (LHH) was favorable, showing that patients were three times more likely to achieve remission than to discontinue treatment due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Appraising esketamine nasal spray for the management of treatment-resistant depression in adults: Number needed to treat, number needed to harm, and likelihood to be helped or harmed. Citrome, L., DiBernardo, A., Singh, J.[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]

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 a post-hoc analysis of 53 patients with major depressive disorder and suicidal ideation, intranasal esketamine showed a significant improvement in depression scores compared to placebo, with a mean difference of -3.8 on the MADRS scale by Day 2.

The safety profile of intranasal esketamine in the Asian subgroup was consistent with the overall ASPIRE I cohort, indicating no unexpected safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of esketamine nasal spray in addition to standard of care in patients with major depressive disorder who have active suicidal ideation with intent: A subgroup analysis of the Asian cohort of ASPIRE I (a randomized, double-blind, placebo-controlled study). Hong, JP., Malek, AZA., Li, CT., et al.[2023]

Esketamine nasal spray combined with an oral antidepressant significantly improves treatment outcomes for patients with treatment-resistant depression, with 5-21 more patients achieving remission and 14-17 more responding compared to those on a placebo during induction therapy.

In maintenance therapy, esketamine reduces the risk of relapse by 19-32 patients, while the incidence of serious adverse events remains low, indicating a favorable benefit-risk profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression. Katz, EG., Hough, D., Doherty, T., et al.[2021]

Ketamine shows promise as a treatment for treatment-resistant depression (TRD), but its use can lead to common adverse events, which are usually temporary.

A case of apnea during a slow sub-anesthetic infusion of ketamine highlights a rare but serious potential side effect, emphasizing the need for careful monitoring and management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. Gómez-Revuelta, M., Fernández-Rodríguez, M., Boada-Antón, L., et al.[2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Aripiprazole: in major depressive disorder. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled study of Org 3770 in depressed outpatients. [2019]

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

Nefazodone in the treatment of severe, melancholic, and recurrent depression. [2018]

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

Open trial of nefazodone among Hispanics with major depression: efficacy, tolerability, and adherence issues. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Appraising esketamine nasal spray for the management of treatment-resistant depression in adults: Number needed to treat, number needed to harm, and likelihood to be helped or harmed. [2021]

6. England pubmed.ncbi.nlm.nih.gov

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

7. 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]

8. Australia pubmed.ncbi.nlm.nih.gov

Efficacy and safety of esketamine nasal spray in addition to standard of care in patients with major depressive disorder who have active suicidal ideation with intent: A subgroup analysis of the Asian cohort of ASPIRE I (a randomized, double-blind, placebo-controlled study). [2023]

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

Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression. [2021]

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

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. [2021]