Enhancing Parasympathetic Activity to Improve Endothelial Dysfunction, Vascular Oxidative Stress in African Americans

NCT04769206 | Recruiting Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: 202376
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Endothelial Dysfunction

Keywords

African American; Flow-mediated dilation (FMD); Vascular Oxidative Stress

Outcome Measures

Primary Outcomes (3)

• FMD

  flow mediated dilation

  From baseline to 3 months

• NADPH activation in PBMC

  NADPH activation as measured by subunits p47phox/gp91 phox in PBMC

  From baseline to 3 months

• NADPH activation in PBMC at TaVNS stimulation

  NADPH activation as measured by subunits p47phox/gp91 phox in PBMC.pre- and post-device stimulation measurements before( baseline) and after lipids infusion at 2 and 4 hours

  From baseline to 120 minutes to 240 minutes

Study Arms (3)

Galantamine

EXPERIMENTAL

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

Drug: Galantamine

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

TENS 7000

ACTIVE COMPARATOR

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

Device: TENS 7000

Interventions

Galantamine DRUG

4mg daily titrating up to 8mg twice a day

Also known as: Razadyne

Galantamine

Placebo DRUG

1 pill a day for 4 weeks, 2 pills a day for 8 weeks

Also known as: sugar pill

Placebo

TENS 7000 DEVICE

The FDA-approved TENS 7000 device will be used for Trans-auricular vagus nerve stimulation (TaVNS) during a period of enhanced vascular oxidative stress. This device will be supplemented with ear clip electrodes. The site of the stimulation for such electrodes are the tragus or concha. The device will have built in safety controls to minimize additional risks to the subjects (as per FDA guidance on stimulators). We will use typical stimulation conditions (30 Hz, 300 µs) and amplitude dependent on perception threshold.

TENS 7000

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• African American women and men
• Age 18 to 60 years old
• BMI \>28

You may not qualify if:

• Individuals with a history of physician diagnosed myocardial infarction, angina, heart failure, stroke, or transient ischemic attack, or who had undergone an invasive procedure for CVD (coronary artery bypass graft, angioplasty, valve replacement, pacemaker placement or other vascular surgeries)
• Uncontrolled hypertension defined as persistent blood pressure \>140/90 despite the use of anti-hypertensive agents.
• Diabetes Mellitus type 1 or type 2, as defined by a fasting plasma glucose of 126 mg/dL or greater hemoglobin A1C (HbA1C) 6.5% or above or the use of anti-diabetic medication
• The use of nitrates.
• The metabolism of galantamine is primarily through the cytochrome P450 system, specifically the CYP2D6 and CYP3A4 isoenzymes. We will exclude subjects who have impaired hepatic function and/or who are currently using strong inhibitors of CYP3A4 and CYP2D6 (e.g. ketoconazole and paroxetine, respectively).
• Pregnancy or breast-feeding. Women of child-bearing potential will be required to have undergone tubal ligation or to be using an oral contraceptive or barrier methods of birth control.
• Post-menopausal women.
• The use of any other central or peripheral acetylcholinesterase inhibitor (donezepil (Aricept(R)), pyridostigmine (Mestinon(R)), rivastigmine (Exelon(R)), tacrine (Cognex(R)).
• First, second or third-degree AV block detected during the screening visit with an ECG
• Seizures or history of seizures.
• Current smokers defined as those who smoked a cigarette in the last 30 days.
• History of recurrent syncope.
• History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack.
• History of cardiac shunts.
• Allergy to eggs or soy.

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (1)

Chaney Johnson

Nashville, Tennessee, 37232, United States

RECRUITING

MeSH Terms

Interventions

Galantamine; Sugars

Intervention Hierarchy (Ancestors)

Amaryllidaceae Alkaloids; Alkaloids; Heterocyclic Compounds; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Carbohydrates

Study Officials

• Cyndya Shibao, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cyndya Shibao, MD

CONTACT

615-936-4584; cyndya.shibao@vumc.org

Chaney Johnson, BSN

CONTACT

(615)322-7568; chaney.r.johnson@vumc.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: February 20, 2021
• First Posted: February 24, 2021
• Study Start: December 20, 2021
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 30, 2029
• Last Updated: May 5, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)