Medication + Nerve Stimulation for HIV

(EVA Trial)

Overseen By Alexandra Nmashie, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: Sympathomimetics, Prokinetics, Antibiotics, others

Disqualifiers: Dysphagia, GI obstruction, Crohn's, others

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for people living with HIV that might reduce inflammation linked to small intestinal bacterial overgrowth (SIBO). It tests a medication called pyridostigmine and a technique called non-invasive vagal nerve stimulation (tVNS) to determine if they can improve gut health and reduce inflammation. Participants will receive either pyridostigmine, undergo vagal nerve stimulation, or take a placebo. The trial seeks individuals with HIV who have been on stable HIV treatment for at least three months and have no other conditions affecting their gut or nerve function. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

The trial requires that you do not take medications with significant autonomic or GI effects, such as sympathomimetics, prokinetics, anti-diarrheals, and antibiotics. If you are on these medications, you may need to stop them to participate.

Do I have to stop taking my current medications for the trial?

The trial requires that you do not take medications with significant effects on the autonomic or gastrointestinal systems, such as certain stimulants, antibiotics, or anti-diarrheals. If you are on such medications, you may need to stop them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that non-invasive vagal nerve stimulation (nVNS) is generally safe and well-tolerated. Studies examining its use for various health issues have not identified any major safety concerns. This method uses electrical currents applied to the ear, avoiding the need for surgery.

Pyridostigmine, a medication approved by the FDA for treating myasthenia gravis, prevents the breakdown of acetylcholine, a chemical essential for muscle function. In individuals with HIV, pyridostigmine has been studied for its potential to reduce inflammation. While generally safe, some may experience mild side effects like nausea or diarrhea.

Both treatments have demonstrated good safety records in previous studies. However, discussing any concerns with the research team remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer innovative approaches for managing HIV. Unlike most treatments that focus on directly targeting the virus, pyridostigmine enhances the immune response by boosting the communication between nerves and muscles, potentially improving overall health in people with HIV. On the other hand, non-invasive vagal nerve stimulation (nVNS) offers a novel method by stimulating the vagus nerve, which may reduce inflammation and improve immune function without medication. These unique mechanisms could complement existing antiretroviral therapies by addressing aspects of HIV's impact that current drugs don't target directly.

What evidence suggests that this trial's treatments could be effective for HIV?

In this trial, participants will receive either pyridostigmine or non-invasive vagal nerve stimulation (nVNS) as separate treatment options. Research has shown that pyridostigmine can aid people with HIV by boosting their immune system. Specifically, studies have found that it increases CD4+ T-cells, crucial for fighting infections, and helps control the virus by reducing the activity of infected T-cells.

For non-invasive vagal nerve stimulation, another treatment option in this trial, the evidence remains less clear. Some studies suggest it might help with depression in people with HIV, but its effects on the vagus nerve in this context are not well understood. More research is needed to confirm if it helps control inflammation related to HIV. ^{3 6 7 8 9}

Who Is on the Research Team?

Jessica Robinson-Papp, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

This trial is for adults with HIV who have a stable treatment regimen, no drug use or pregnancy, and no other conditions affecting the nervous system or gastrointestinal tract. Participants must not smoke for 24 hours before tests and can't be on certain medications that affect the autonomic system or digestion.

Inclusion Criteria

Documentation of HIV-1 infection

Urine test negative for stimulants and opiates/opioids and pregnancy test (if applicable)

I don't have conditions like Parkinson's, diabetes, or ulcers that affect my digestion, except possibly HIV.

Exclusion Criteria

I have trouble swallowing food or pills.

I haven't had GI surgery in the last 3 months, don't have Crohn's or diverticulitis, and don't use devices like pacemakers.

I have no history of brain issues, abnormal neck anatomy, or recent VNS.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo autonomic function tests, hydrogen/methane breath testing, Wireless Motility Capsule testing, blood draw, and collection of stool samples and oral swabs

1-2 weeks

Treatment

Participants receive 8 weeks of pyridostigmine or placebo, or undergo 8 weeks of non-invasive vagal nerve stimulation

8 weeks

Follow-up

Participants are retested for autonomic function, hydrogen/methane breath testing, Wireless Motility Capsule testing, blood draw, and collection of stool samples and oral swabs

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Non-invasive Vagal Nerve Stimulation
• Placebos
• Pyridostigmine

Trial Overview

The study examines if pyridostigmine medication and non-invasive vagal nerve stimulation can improve gut health and reduce inflammation in people with HIV. It explores how vagus nerve dysfunction might contribute to these issues.

How Is the Trial Designed?

Group I: nVNS Experimental Treatment 1 Intervention

PLWH to undergo non-invasive vagal nerve stimulation

Group II: PLWH Active Control 1 Intervention

People living with HIV (HIV)

Group III: Healthy Controls Active Control 1 Intervention

Healthy controls who do not have HIV

Group IV: Pyridostigmine Active Control 1 Intervention

PLWH on pyridostigmine 30mg PO TID

Group V: Placebo Placebo Group 1 Intervention

PLWH on placebo

Non-invasive Vagal Nerve Stimulation is already approved in United States, European Union for the following indications:

Approved in United States as gammaCore for:

• Cluster headache
• Migraine

Approved in European Union as gammaCore for:

• Cluster headache
• Migraine
• Hemicrania continua

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive and cost-effective method for modulating the vagus nerve, making it a promising alternative to traditional surgical vagus nerve stimulation.

taVNS allows for easy and safe administration, with considerations for proper electrode placement and individual dosing based on perception thresholds, which enhances its potential for treating various central and peripheral diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. Badran, BW., Yu, AB., Adair, D., et al.[2020]

Transcutaneous vagus nerve stimulation (tVNS) was found to significantly increase salivary alpha amylase (SAA) levels and reduce the decline of salivary cortisol in healthy participants, indicating a modulation of hormonal indices related to noradrenergic function.

However, tVNS did not show any significant effects on psychophysiological measures such as P3 amplitude or pupil size, suggesting that while it may influence hormonal responses, it does not impact certain cognitive or physiological indices in the same way.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The neuromodulatory and hormonal effects of transcutaneous vagus nerve stimulation as evidenced by salivary alpha amylase, salivary cortisol, pupil diameter, and the P3 event-related potential. Warren, CM., Tona, KD., Ouwerkerk, L., et al.[2019]

In a small study of six very young children (average age 20.5 months) who underwent vagus nerve stimulation (VNS) for epilepsy, 83% experienced a significant reduction in seizure frequency, with 33% becoming seizure-free.

No adverse effects or complications were reported from the VNS procedure, suggesting it is a safe option for treating life-threatening epilepsy in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in children less than 5 years old. Blount, JP., Tubbs, RS., Kankirawatana, P., et al.[2018]

Auricular transcutaneous vagus nerve stimulation (atVNS) significantly enhances memory persistence in naïve mice, indicating its potential as a cognitive enhancer.

In a mouse model of intellectual disability (Fmr1 knockout), atVNS effectively normalized memory deficits, suggesting it could be a promising intervention for cognitive disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Auricular transcutaneous vagus nerve stimulation improves memory persistence in naïve mice and in an intellectual disability mouse model. Vázquez-Oliver, A., Brambilla-Pisoni, C., Domingo-Gainza, M., et al.[2020]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

Vagus nerve stimulation (VNS) therapy can effectively control seizures in conditions like epilepsy and may also improve mood and cognitive functions, with a surgical success rate of 50-60% for seizure control.

While VNS therapy has potential benefits, it carries risks of both early and late complications, including infections, vocal cord paralysis, and laryngopharyngeal dysfunction, which occurs in about 66% of patients but is usually temporary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation: Surgical technique of implantation and revision and related morbidity. Giordano, F., Zicca, A., Barba, C., et al.[2022]

Vagus nerve stimulation (VNS) shows promising efficacy as an add-on treatment for treatment-refractory depression, with 29 out of 33 studies focusing on its effects in unipolar or bipolar major depressive disorder.

However, the evidence for VNS in other psychiatric disorders like schizophrenia, Alzheimer's disease, and OCD is limited and inconclusive, indicating a need for more controlled studies in these areas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in psychiatry: a systematic review of the available evidence. Cimpianu, CL., Strube, W., Falkai, P., et al.[2018]

In the PRESTO trial involving 248 patients with episodic migraine, non-invasive vagus nerve stimulation (nVNS) significantly increased the likelihood of achieving pain relief at 60 and 120 minutes post-treatment compared to a sham device, demonstrating its efficacy as an acute treatment.

The safety profile of nVNS was strong, with low incidence of adverse events and no serious adverse events reported, suggesting it is a reliable option for migraine treatment that can be used alongside traditional medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized, sham-controlled, double-blind PRESTO trial. Martelletti, P., Barbanti, P., Grazzi, L., et al.[2020]

Transcutaneous vagus nerve stimulation (tVNS) significantly reduces seizure frequency in patients with drug-resistant epilepsy, based on a meta-analysis of three studies involving 280 patients.

tVNS appears to have a low incidence of adverse effects, with headaches being the most common, making it a safer alternative for patients who cannot undergo invasive procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation for the treatment of drug-resistant epilepsy: a meta-analysis and systematic review. Wu, K., Wang, Z., Zhang, Y., et al.[2022]

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A group of independent scientists who monitor the safety and scientific integrity of a clinical trial. The DMC can recommend to the sponsor that ...