AXS-05 for Alzheimer's Disease Agitation

Recruiting at 16 trial locations

Age: 65+

Sex: Any

Trial Phase: Phase 3

Sponsor: Axsome Therapeutics, Inc.

Disqualifiers: Hospitalized, Nursing home, Living alone, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 25 weeks

139 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but if you started a new medication since enrolling in the previous studies, it might be a concern if it poses a safety risk with AXS-05.

What data supports the effectiveness of the drug AXS-05 for Alzheimer's Disease Agitation?

AXS-05, a combination of dextromethorphan and bupropion, has been shown to be effective in treating major depressive disorder, with significant improvements in depression scores and high remission rates. While this data is for depression, it suggests potential benefits for Alzheimer's-related agitation due to the drug's impact on brain signaling. ^{1 2 3 4 5}

Is AXS-05 (Dextromethorphan-Bupropion) safe for humans?

AXS-05, also known as Auvelity, has been approved for treating major depressive disorder in adults. It may increase the risk of suicidal thoughts in young people and can cause seizures, especially at higher doses. Common side effects include dizziness, nausea, headache, and dry mouth. ^{1 2 3 6 7}

What makes the drug AXS-05 unique for treating agitation in Alzheimer's disease?

AXS-05 is unique because it combines dextromethorphan, which affects brain receptors involved in mood and behavior, with bupropion, which helps increase the effectiveness of dextromethorphan. Unlike other treatments, it is being investigated specifically for Alzheimer's-related agitation, and there are currently no FDA-approved drugs for this condition. ^{1 2 3 8 9}

What is the purpose of this trial?

The primary objective of this open-label extension trial is to evaluate the long-term safety of AXS-05 for the treatment of Alzheimer's disease agitation in subjects that participated in ADVANCE-2 and ACCORD-2.

Eligibility Criteria

This trial is for individuals who have Alzheimer's disease with symptoms of agitation and participated in previous ADVANCE-2 or ACCORD-2 studies. It aims to understand the long-term safety of AXS-05, a medication intended to manage these symptoms.

Inclusion Criteria

Completed the treatment period in Study AXS-05-AD-304 or exited from Study AXS-05-AD-303 due to study completion

My caregiver agrees to follow the study's requirements and help me with my treatment.

Exclusion Criteria

I am currently living in a mental health facility, nursing home, or by myself.

Caregiver is unwilling or unable, in the opinion of the Investigator, to comply with study instructions

Any concurrent medical condition that might interfere with the conduct of the study, confound the interpretation of study results, or endanger the subject's well-being

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AXS-05 for the treatment of Alzheimer's disease agitation

25 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• AXS-05

Trial Overview The study tests the ongoing safety of AXS-05 (a combination of dextromethorphan and bupropion) in managing agitation associated with Alzheimer's over an extended period. This open-label trial allows all participants to receive the drug.

Participant Groups

Group I: Open-Label Experimental Treatment 1 Intervention

Experimental: AXS-05 (dextromethorphan-bupropion) up to 25 weeks

AXS-05 is already approved in United States for the following indications:

Approved in United States as Auvelity for:

• Major depressive disorder

Who Is Running the Clinical Trial?

Axsome Therapeutics, Inc.

Lead Sponsor

Trials

34

Recruited

11,600+

Findings from Research

Dextromethorphan/bupropion, a fixed-dose combination medication, was approved in August 2022 for treating major depressive disorder (MDD) in adults, highlighting its efficacy as a new treatment option.

The combination works by utilizing dextromethorphan as an NMDA receptor antagonist and sigma-1 receptor agonist, while bupropion enhances the bioavailability of dextromethorphan, potentially improving therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dextromethorphan/Bupropion: First Approval. Keam, SJ.[2022]

In a phase 3 trial involving 327 patients with major depressive disorder, AXS-05 (dextromethorphan-bupropion) significantly improved depressive symptoms compared to placebo, with effects noticeable as early as week 1.

The treatment led to a remission rate of 39.5% compared to 17.3% for placebo, and was generally well tolerated, with no serious side effects like weight gain or increased sexual dysfunction reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). Iosifescu, DV., Jones, A., O'Gorman, C., et al.[2022]

In a phase 2 trial involving 80 patients with major depressive disorder, dextromethorphan-bupropion (AXS-05) showed a significantly greater reduction in depression symptoms compared to bupropion, with a mean change in MADRS score of -13.7 points versus -8.8 points over 6 weeks.

Dextromethorphan-bupropion also resulted in higher remission rates (46.5% vs. 16.2% at week 6) and response rates (60.5% vs. 40.5% at week 6), while being generally well tolerated with minimal adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. Tabuteau, H., Jones, A., Anderson, A., et al.[2022]

Dextromethorphan-bupropion (Auvelity) is an FDA-approved treatment for major depressive disorder that has shown significant efficacy in reducing depression scores in phase 3 trials, with effects noticeable within two weeks.

The treatment is well-tolerated, with mild-to-moderate side effects, and long-term studies indicate high remission rates of nearly 70% and response rates over 80%, making it a promising option for fast-acting depression relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dextromethorphan-bupropion (Auvelity) for the Treatment of Major Depressive Disorder. McCarthy, B., Bunn, H., Santalucia, M., et al.[2023]

Auvelity, a combination of dextromethorphan and bupropion, is approved for treating major depressive disorder in adults, but it carries a boxed warning for increased risk of suicidal thoughts and behaviors in younger patients.

Common side effects include dizziness, nausea, and headache, with a risk of seizures at higher doses, highlighting the importance of careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Combination Drug for Depression. Aschenbrenner, DS.[2023]

Citalopram has shown promising efficacy in treating agitation in Alzheimer's disease dementia, potentially benefiting from a class effect seen in selective serotonin reuptake inhibitors, but concerns about its cardiac side effects have limited its use.

The article reviews safety and efficacy data for both citalopram and escitalopram, providing practical recommendations and risk mitigation strategies to enhance their use in clinical practice for managing agitation in dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

When and How to Treat Agitation in Alzheimer's Disease Dementia With Citalopram and Escitalopram. Aga, VM.[2022]

Sublingual dexmedetomidine has a favorable efficacy profile for treating agitation in adults with schizophrenia or bipolar disorder, with a number needed to treat of 3 for significant response at 2 hours post-dose in both conditions.

The treatment's safety profile is also acceptable, as the number needed to harm for adverse events is generally greater than 10, except for somnolence, which has a number needed to harm of 7, indicating that the benefits outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sublingual Dexmedetomidine for Agitation Associated with Schizophrenia or Bipolar Disorder: A Post Hoc Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed. Citrome, L., Risinger, R., Rajachandran, L., et al.[2023]

References

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

Dextromethorphan/Bupropion: First Approval. [2022]

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

Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). [2022]

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

Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. [2022]

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

Dextromethorphan-bupropion (Auvelity) for the Treatment of Major Depressive Disorder. [2023]

5. England pubmed.ncbi.nlm.nih.gov

R- and S-citalopram concentrations have differential effects on neuropsychiatric scores in elders with dementia and agitation. [2022]

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

New Combination Drug for Depression. [2023]

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

When and How to Treat Agitation in Alzheimer's Disease Dementia With Citalopram and Escitalopram. [2022]

8. England pubmed.ncbi.nlm.nih.gov

AXS-05: an investigational treatment for Alzheimer's disease-associated agitation. [2022]

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

Sublingual Dexmedetomidine for Agitation Associated with Schizophrenia or Bipolar Disorder: A Post Hoc Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed. [2023]