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

55 Participants Needed

Trial Summary

What is the purpose of this trial?

The study team's prior research has shown that dysfunction of a specific nerve, called the vagus nerve, is associated with small intestinal bacterial overgrowth (SIBO), and that SIBO is associated with signs of inflammation in the blood of people living with HIV (PLWH). This research will explore pathways linking vagal dysfunction to inflammation in HIV, focusing on the gastrointestinal tract, and study whether a medication called pyridostigmine and stimulation of the vagus nerve are beneficial therapies.

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.

What data supports the idea that Medication + Nerve Stimulation for HIV is an effective treatment?

The available research shows that non-invasive vagus nerve stimulation (VNS) has been explored for its potential benefits in various conditions, such as epilepsy, depression, and intellectual disabilities. However, there is no specific data provided here that directly supports the effectiveness of Medication + Nerve Stimulation for HIV. The studies mention potential benefits in other areas, but more research is needed to determine its effectiveness for HIV treatment. ^{1 2 3 4 5}

What data supports the effectiveness of this treatment for HIV?

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique that has shown promise in treating conditions like epilepsy and depression by potentially increasing norepinephrine activity in the brain. While specific data on its effectiveness for HIV is not available, its use in other conditions suggests it may have beneficial effects on the nervous system. ^{1 2 3 4 5}

What safety data exists for Medication + Nerve Stimulation for HIV?

The safety data for non-invasive vagus nerve stimulation (nVNS) and transcutaneous vagus nerve stimulation (tVNS) indicates that these techniques are generally safe and well-tolerated. The PRESTO trial showed nVNS to be safe for treating migraines. A systematic review and meta-analysis of transcutaneous auricular vagus nerve stimulation (taVNS) found it to be safe with mild and transient adverse effects like ear pain, headache, and tingling. No severe adverse events were causally linked to taVNS, and the incidence of adverse events was low. These findings suggest that nerve stimulation techniques are safe for clinical use. ^{1 5 6 7 8}

Is transcutaneous vagus nerve stimulation (tVNS) safe for humans?

Transcutaneous vagus nerve stimulation (tVNS) is generally considered safe, with mild and temporary side effects like ear pain, headache, and tingling. A systematic review found no significant difference in the risk of adverse events between active tVNS and control groups, and no severe adverse events were linked to tVNS. ^{1 5 6 7 8}

Is the treatment Non-invasive Vagal Nerve Stimulation, Pyridostigmine a promising treatment for HIV?

Yes, Non-invasive Vagal Nerve Stimulation (tVNS) is a promising treatment because it is a new, non-invasive method that can be used to help manage various health conditions. It is safe, inexpensive, and portable, making it accessible for many people. It has shown positive effects in treating conditions like epilepsy and depression, which suggests it could be beneficial for other diseases like HIV. ^{1 4 5 7 9}

How is the treatment of non-invasive vagal nerve stimulation and pyridostigmine for HIV different from other treatments?

This treatment is unique because it combines a non-invasive technique called transcutaneous vagus nerve stimulation (tVNS) with the drug pyridostigmine. Unlike traditional treatments that may involve surgery or more invasive methods, tVNS is a safe, portable, and inexpensive way to stimulate the vagus nerve, potentially improving central and peripheral health without the need for surgical implantation. ^{1 4 5 7 9}

Research Team

Jessica Robinson-Papp, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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 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]

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]

References

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

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. [2020]

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

Auricular transcutaneous vagus nerve stimulation improves memory persistence in naïve mice and in an intellectual disability mouse model. [2020]

3. Austria pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in psychiatry: a systematic review of the available evidence. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in children less than 5 years old. [2018]

5. United States 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. [2019]

6. England 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. [2020]

7. Australia pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation for the treatment of drug-resistant epilepsy: a meta-analysis and systematic review. [2022]

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

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. [2023]

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

Vagus nerve stimulation: Surgical technique of implantation and revision and related morbidity. [2022]