Rivastigmine for Delirium

(RIVA-AM Trial)

Overseen By Kevin Baumgartner, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Sodium bicarbonate, Vasopressors

Disqualifiers: Seizure disorder, Asthma, COPD, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 8-36 hours

42 Participants Needed

Trial Summary

What is the purpose of this trial?

Antimuscarinic delirium (AMD) is a common and dangerous toxicology condition caused by poisoning by medications and other chemicals that block muscarinic receptors. Physostigmine, the standard antidote for AMD, currently has very limited availability in the United States due to an interruption of production. Recent case reports and small observational studies suggest that rivastigmine might be useful in the treatment of AMD, but there is not direct prospective evidence comparing rivastigmine to physostigmine or supportive care. In order to investigate the effectiveness of rivastigmine, the investigators propose a randomized, placebo-controlled clinical trial of rivastigmine for AMD. The investigators hypothesize that patients treated with rivastigmine for antimuscarinic delirium will experience more rapid resolution of agitation and delirium than those treated with placebo.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug Rivastigmine for treating delirium?

Rivastigmine has been shown to improve cognitive function in patients with Alzheimer's disease, which suggests it may help with similar symptoms in delirium, although direct evidence for delirium is not provided. ^{1 2 3 4 5}

How is the drug rivastigmine unique for treating delirium?

Rivastigmine is unique because it is available as a transdermal patch, which allows for smooth and continuous delivery of the drug, potentially increasing treatment compliance and reducing side effects compared to oral medications. ^{1 3 6 7 8}

Research Team

Kevin Baumgartner, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for individuals experiencing antimuscarinic delirium, a type of confusion and agitation due to certain medication or chemical poisoning. Details on who can join are not provided, but typically participants must meet specific health criteria.

Inclusion Criteria

Diagnosis of antimuscarinic delirium by history and physical examination, in the opinion of the treating attending toxicologist

I am at least 10 years old.

I am experiencing significant agitation and confusion that could improve with specific treatment.

Exclusion Criteria

I am under 10 years old.

Patient is pregnant or a ward of the state

Inability to safely tolerate oral medication, in the judgement of the treating attending physician

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive rivastigmine or placebo for antimuscarinic delirium, with doses administered as needed for ongoing delirium or agitation

8-36 hours

Continuous monitoring during treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of agitation and delirium

1 week

Regular assessments every 2 hours until sustained recovery

Treatment Details

Interventions

• Rivastigmine

Trial Overview The study tests if rivastigmine helps treat antimuscarinic delirium faster than a placebo. Participants will be randomly assigned to receive either rivastigmine or an inactive substance (placebo) in this controlled trial.

Participant Groups

Group I: Rivastigmine Experimental Treatment 1 Intervention

Patients in the rivastigmine arm will receive rivastigmine 3mg by mouth once, followed by rivastigmine 1.5mg by mouth every 1 hour as needed for ongoing delirium or agitation (at the discretion of the treating physician), for up to three doses.

Group II: Placebo Placebo Group 1 Intervention

Patients in the placebo arm will receive oral placebo by mouth once, followed by oral placebo every 1 hour as needed for ongoing delirium or agitation (at the discretion of the treating physician), for up to three doses.

Rivastigmine is already approved in European Union, United States for the following indications:

Approved in European Union as Exelon for:

• Alzheimer's Disease
• Parkinson's Disease Dementia

Approved in United States as Exelon for:

• Alzheimer's Disease
• Parkinson's Disease Dementia

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

American Academy of Clinical Toxicology

Collaborator

Trials

3

Recruited

100+

American Academy of Clinical Toxicology

Collaborator

Trials

3

Recruited

100+

Findings from Research

In a 52-week study involving patients with mild to moderately severe Alzheimer's disease, those treated with rivastigmine tartrate showed significantly better cognitive function compared to those who received a placebo.

The study included an initial 26-week double-blind phase followed by a 26-week open-label extension, demonstrating the sustained efficacy of rivastigmine over a full year.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Farlow, M., Anand, R., Messina, J., et al.[2022]

A study involving 40 healthy men demonstrated that the generic formulation of rivastigmine is bioequivalent to the brand Exelon, with similar pharmacokinetic profiles as shown by comparable AUC and Cmax values.

Both the generic and reference formulations were well tolerated by participants, indicating that the generic version is a safe alternative to the brand-name drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence Study of Rivastigmine 6 mg Capsules (Single Dose) in Healthy Volunteers. Abhyankar, D., Shedage, A., Gole, M., et al.[2018]

Rivastigmine tartrate is effective in improving or maintaining cognitive function, daily living activities, and behavior in patients with mild to moderate Alzheimer's disease, based on clinical trials lasting up to 52 weeks.

The most common side effects are mild to moderate gastrointestinal issues, and treatment may lead to cost savings in care, particularly by delaying the need for institutionalization, especially in patients with moderate Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of rivastigmine: a reversible cholinesterase inhibitor. Williams, BR., Nazarians, A., Gill, MA.[2022]

In a study of 892 patients with probable Alzheimer's disease, both rivastigmine patches and capsules significantly improved activities of daily living (ADLs) compared to placebo after 24 weeks, indicating their efficacy in managing symptoms.

Rivastigmine patches showed a lower incidence of gastrointestinal side effects compared to capsules, making them a safer alternative for patients who may be sensitive to such side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of rivastigmine patch and capsules on activities of daily living in Alzheimer's disease. Grossberg, G., Meng, X., Olin, JT.[2015]

Rivastigmine, whether administered as a patch or capsule, significantly improves cognitive function in patients with mild to severe Alzheimer's disease compared to placebo, as shown in a meta-analysis of 17 studies.

The rivastigmine patch is more effective than the capsule in reducing cognitive decline, as indicated by a greater improvement in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effectiveness of rivastigmine patch or capsule for mild-to-severe Alzheimer's disease: a meta-analysis. Su, J., Liu, Y., Liu, Y., et al.[2018]

In the phase III OPTIMA trial, patients with mild to moderate Alzheimer's disease showed significant benefits in functional and cognitive decline when their rivastigmine dose was increased from a 10 cm² patch to a 15 cm² patch after 24 weeks.

The 15 cm² patch was generally well tolerated, with fewer patients discontinuing treatment due to adverse events compared to the 10 cm² patch, indicating a favorable benefit-risk profile for increasing the dose in patients who had previously experienced decline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rivastigmine transdermal patch 13.3 mg/24 h: a review of its use in the management of mild to moderate Alzheimer's dementia. Frampton, JE.[2021]

The study demonstrated that the new rivastigmine transdermal patch (RIV-TDS) is bioequivalent to the marketed Exelon patch, meaning they deliver the same amount of the drug into the bloodstream, which is important for consistent treatment of Alzheimer's disease.

RIV-TDS showed better skin adhesion and tolerability compared to the reference product, suggesting it may enhance patient compliance and comfort during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects. Morte, A., Vaqué, A., Iniesta, M., et al.[2022]

An 87-year-old male with dementia experienced severe adverse effects, including nausea, vomiting, and renal failure, after mistakenly applying six rivastigmine patches simultaneously, leading to his death from uremia due to dehydration.

This case highlights the critical need for clear labeling and instructions for rivastigmine patches to prevent medication errors, emphasizing that only one patch should be applied at a time to avoid overdose and serious health consequences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fatal outcome after unintentional overdosing of rivastigmine patches. Lövborg, H., Jönsson, AK., Hägg, S.[2019]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. [2022]

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

Bioequivalence Study of Rivastigmine 6 mg Capsules (Single Dose) in Healthy Volunteers. [2018]

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

A review of rivastigmine: a reversible cholinesterase inhibitor. [2022]

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

Impact of rivastigmine patch and capsules on activities of daily living in Alzheimer's disease. [2015]

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

Long-term effectiveness of rivastigmine patch or capsule for mild-to-severe Alzheimer's disease: a meta-analysis. [2018]

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

Rivastigmine transdermal patch 13.3 mg/24 h: a review of its use in the management of mild to moderate Alzheimer's dementia. [2021]

7. France pubmed.ncbi.nlm.nih.gov

Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects. [2022]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

A fatal outcome after unintentional overdosing of rivastigmine patches. [2019]