Galantamine for Endothelial Dysfunction

Recruiting at 1 trial location

Overseen By Annet Kirabo, DVM PHD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vanderbilt University Medical Center

Must not be taking: Nitrates, CYP3A4 inhibitors

Disqualifiers: Heart disease, Hypertension, Diabetes, Seizures, others

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

Compensation: Varies

Number of Visits: 10

Duration: 12 weeks

88 Participants Needed

Trial Summary

What is the purpose of this trial?

Specific Aim 1: To test the hypothesis that prolonged (3-month) treatment with galantamine inhibits NADPH IsoLG-protein adducts formation and improves markers of endothelial cell (EC) dysfunction in AAs. Aim 1a: The investigators will determine if galantamine inhibits NADPH IsoLG-protein adducts formation, superoxide production, and immune cell activation compared to placebo. For this purpose, the investigators will study peripheral blood mononuclear cell (PBMC), a critical source of systemic oxidative stress, collected from study participants. Aim 1b: The investigators will determine if galantamine reduces intracellular Iso-LGs, ICAM-1, and 3-nitrotyrosine, a marker of vascular oxidative stress, in ECs harvested from study participants. Specific Aim 2: To determine if prolonged (3-month) treatment with galantamine improves endothelial dysfunction as measured by vascular reactivity in AAs. The investigators will measure vascular reactivity in response to ischemia in two vascular beds: (a) in conduit arteries (brachial artery) using brachial artery diameter flow-mediated dilation (FMD), and (b) in the microvasculature (MBV) using contrast-enhanced ultrasonography in skeletal muscle. Sub-study (optional) Will study the effect of trans-auricular vagus nerve stimulation (TaVNS) during a period of enhanced vascular oxidative stress This proposal will study a novel mechanism that could alter the oxidative and immunogenic responses that contributes to endothelial dysfunction in AAs and will offer a potential pathway for the development of more effective therapies aimed at decreasing the progression of endothelial dysfunction to cardiovascular disease in this population.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as nitrates, strong inhibitors of CYP3A4 and CYP2D6 (like ketoconazole and paroxetine), and any other central or peripheral acetylcholinesterase inhibitors. If you are on these medications, you would need to stop them to participate in the trial.

Is Galantamine safe for human use?

Galantamine has been studied for Alzheimer's disease and is generally considered safe, having received regulatory approval in many countries, including the United States and the European Union. It has been shown to have antioxidant and neuroprotective effects, which may contribute to its safety profile. ^{1 2 3 4 5}

How is the drug Galantamine unique for treating endothelial dysfunction?

Galantamine is unique because it not only inhibits acetylcholinesterase (an enzyme that breaks down a neurotransmitter called acetylcholine) but also acts as an antioxidant, potentially reducing oxidative stress, which is linked to various diseases. This dual action might offer a novel approach to treating endothelial dysfunction, which currently lacks standard treatments. ^{1 2 4 5 6}

Research Team

Cyndya A Shibao, MD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for African American men and women aged 18 to 60 with a BMI over 28. It's not suitable for those with liver or kidney issues, anemia, diabetes, certain medication use, pregnancy, substance abuse, uncontrolled hypertension, serious heart conditions or neurologic diseases.

Inclusion Criteria

I am an African American woman or man.

You have a body mass index (BMI) higher than 28, which means you are overweight.

I am between 18 and 60 years old.

Exclusion Criteria

My blood pressure is often above 140/90 despite taking medication.

I use nitrates for my condition.

You have taken any experimental medication within the month before the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Randomization and Initial Assessment

Participants undergo initial assessments including EKG, blood tests, and are randomized to treatment or placebo

1 day

1 visit (in-person)

Treatment

Participants receive galantamine or placebo for 3 months with dose titration and telemedicine follow-ups

12 weeks

3 visits (in-person), 3 visits (telemedicine)

Safety Follow-up

Participants attend outpatient clinic visits for safety monitoring and dose titration

8 weeks

3 visits (in-person)

Final Assessment

Final assessment of endpoints including repeated procedures from initial assessment

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Sub-study (Optional)

Evaluation of trans-auricular vagus nerve stimulation effects on vascular oxidative stress

1 day

1 visit (in-person)

Treatment Details

Interventions

• Galantamine
• Placebo

Trial Overview The study tests if galantamine can reduce oxidative stress and improve endothelial function in African Americans over three months. Participants will be compared to a placebo group to see if there are changes in blood markers and vascular reactivity.

Participant Groups

Group I: Galantamine Experimental Treatment 1 Intervention

Galantamine 16mg/day - titrating: 4mg once a day for 2 weeks, titrate to 8mg once a day for 2 weeks, then 8mg twice a day for 8 more weeks

Group II: TENS 7000 Active Control 1 Intervention

Substudy: the effect of trans-auricular vagus nerve stimulation (TaVNS) will be done by FDA-approved TENS 7000 device and during a period of enhanced vascular oxidative stress

Group III: Placebo Placebo Group 1 Intervention

placebo (micro crystalline cellulose) - 1 pill once daily for 4 weeks, then 2 pills daily for 8 weeks

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

Approved in United States as Razadyne for:

• Mild to moderate dementia associated with Alzheimer's Disease

Approved in European Union as Reminyl for:

• Mild to moderate dementia associated with Alzheimer's Disease

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Findings from Research

In a 12-week study involving 82 Alzheimer's patients, a 1-week dose titration of extended-release galantamine (GAL-ER) was found to be generally safe and well tolerated, although there was a higher incidence of gastrointestinal side effects compared to a longer titration period.

Patients showed a slight improvement in cognitive function, with Mini-Mental State Examination scores increasing by 1.8 points at week 4 and 1.9 points at week 12, suggesting that the 1-week titration could help with medication adherence while managing safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-week dose titration of extended release galantamine in patients with Alzheimer's disease. Scharre, DW., Shiovitz, T., Zhu, Y., et al.[2013]

Galantamine has shown significant efficacy in improving cognitive function and global ratings in patients with Alzheimer's disease, particularly at doses of 16-32 mg over treatment durations of 3 to 6 months, based on a review of seven trials involving a total of 7460 participants.

The safety profile of galantamine is similar to other cholinesterase inhibitors, with gastrointestinal symptoms being the most common side effects, and a dose of 16 mg/day appears to be the best tolerated, suggesting it may be the preferred starting dose for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Galantamine for Alzheimer's disease. Olin, J., Schneider, L.[2020]

Galantamine, an acetylcholinesterase inhibitor, has shown significant efficacy in improving cognitive function and global ratings in patients with Alzheimer's disease, particularly at doses of 16-32 mg/day over treatment durations of 3 to 6 months, based on a systematic review of 7 trials involving a total of several hundred participants.

The safety profile of galantamine is similar to other cholinesterase inhibitors, with gastrointestinal side effects being the most common, and a dose of 16 mg/day appears to be the best tolerated, making it a preferable starting dose for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Galantamine for Alzheimer's disease. Olin, J., Schneider, L.[2020]

Galantamine and its derivatives show significant antioxidant and neuroprotective effects by reducing oxidative stress, which is linked to various diseases, including Alzheimer's and Parkinson's.

The mechanisms of action include scavenging reactive oxygen species, preventing mitochondrial damage, and enhancing acetylcholine levels, which together help protect neurons from cytotoxic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antioxidant activity of galantamine and some of its derivatives. Tsvetkova, D., Obreshkova, D., Zheleva-Dimitrova, D., et al.[2019]

Galantamine, an acetylcholinesterase inhibitor, has shown significant cognitive and global benefits in patients with Alzheimer's disease, particularly at daily doses of 24-32 mg over treatment durations of 3 to 6 months, based on a review of seven trials involving various durations and doses.

While galantamine is effective, it has gastrointestinal side effects similar to other cholinesterase inhibitors, and higher doses (32 mg/day) may lead to higher discontinuation rates, although a slower titration can mitigate this risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Galantamine for Alzheimer's disease. Olin, J., Schneider, L.[2018]

In a study involving 788 patients with vascular dementia, galantamine significantly improved cognitive function compared to placebo after 26 weeks, as measured by the ADAS-cog/11 scale.

While galantamine showed benefits in cognition and executive function, it did not demonstrate a significant improvement in daily living activities compared to placebo, indicating that while it is effective for cognitive symptoms, its impact on overall daily functioning may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Galantamine treatment of vascular dementia: a randomized trial. Auchus, AP., Brashear, HR., Salloway, S., et al.[2022]

References

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

One-week dose titration of extended release galantamine in patients with Alzheimer's disease. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Galantamine for Alzheimer's disease. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Galantamine for Alzheimer's disease. [2020]

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

Antioxidant activity of galantamine and some of its derivatives. [2019]

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

Galantamine for Alzheimer's disease. [2018]

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

Galantamine treatment of vascular dementia: a randomized trial. [2022]