HIVPhase 1/2EVANCT04353778

Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV

A Phase 1/2 study testing Pyridostigmine and non-invasive vagal nerve stimulation in people with HIV and Non-HIV, run by Icahn School of Medicine at Mount Sinai at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for: HIV, Non-HIV, Vagus Nerve Dysfunction
What is being tested?: Pyridostigmine and non-invasive vagal nerve stimulation
Type of treatment: Surgery or procedure
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 215 participants
Where: 1 siteUnited States
Study dates: 3 Aug 2020to 27 Mar 2026
Phase: Phase 1/2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

Greater than or equal to18 years old (18 to 64 Years, 65 Years and Over)
Documentation of HIV-1 infection
Stable CART for greater or equal to 3 months
HIV-1 viral load <100 copies/ml (within 3m)
No diagnosis known to cause autonomic or GI dysfunction other than HIV (e.g. Parkinson's disease, diabetes, peptic ulcer disease, infectious diarrhea)
Willing to refrain from nicotine use for 24h prior to all testing

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No contraindication to autonomic testing (e.g. uncontrolled glaucoma, heart rate not under sinus control)
No medications with significant autonomic or GI effects (e.g. sympathomimetics, prokinetics, anti-diarrheals, antibiotics)
Urine test negative for stimulants and opiates/opioids and pregnancy test (if applicable)

Who cannot join

Dysphagia to food or pills
Known or suspected obstructive disease of the GI tract (e.g. bezoar, strictures, fistulae, physiologic GI obstruction)
GI surgery within 3m, Crohn's disease, diverticulitis, any electromechanical medical device (e.g. pacemaker, infusion pump).
Contraindication to pyridostigmine (e.g. mechanical intestinal or urinary obstruction, hypersensitivity to pyridostigmine, cardiac arrhythmias, asthma, chronic obstructive pulmonary disease); use of pyridostigmine within the past 6m.
History of intracranial aneurysm/hemorrhage, brain tumor, abnormal neck anatomy, or implants or metal hardware near site of stimulation; exposure to VNS within the past 6m.

Trial locations and contacts

1 site in 1 country.

United States1 site

Icahn School of Medicine at Mount Sinai
New York, New York, 10029

Other trials in United States

About this study

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.

Read the detailed description

Objectives Aim 1: To elucidate mechanisms linking VD, SIBO and chronic inflammation in PLWH. PLWH (N=150) will undergo autonomic function tests (AFTs) for VD, hydrogen/methane breath testing (HBT) for SIBO, Wireless Motility Capsule (WMC, SmartPill) testing for GI transit times and pH measurements, blood draw for quantification of inflammatory mediators, and collection of stool samples and oral swabs for characterization of the GI microbiome.

Hypothesis 1a (primary): The relationship between VD and SIBO in HIV is mediated by prolonged small bowel transit time (SBTT) and hypochlorhydria.

Hypothesis 1b (exploratory): There is an additional pathway linking VD and elevated IL-6 in PLWH which is independent of SIBO and bacterial translocation.

Aim 2: To determine whether the relationship between VD and SIBO is modified by the presence of HIV-infection. HIV-infection results in disruption of the GI mucosal barrier,5 which could make PLWH more vulnerable to adverse GI effects of VD. HIV-uninfected controls (N=100), age and gender matched to the PLWH from Aim 1, will undergo the same assessment as the PLWH. The study team will test for effect modification of the VD-SIBO relationship by HIV status, using logistic regression to examine the interaction between VD and HIV.

Aim 3: To establish vagal pathways as a viable treatment target for individuals with well-controlled HIV. PLWH with VD, SIBO and/or prolonged SBTT (N=96) will be identified from the Aim 1 cohort. The first 86 eligible patients will be randomized to 8 weeks of pyridostigmine versus placebo; the remaining 10 will receive 8 weeks of open-label noninvasive vagal nerve stimulation (nVNS) to assess feasibility. All patients will then be retested (AFTs, HBT, SmartPill, blood draw, stool samples and oral swabs).

Hypothesis 3a (primary): Eight weeks of low-dose pyridostigmine (30mg PO TID) will reduce SIBO as compared to placebo in PLWH. Hypothesis 3b (exploratory): Non-invasive VNS is safe, well tolerated and acceptable to PLWH.

Conditions: HIV, Non-HIV, Vagus Nerve Dysfunction
Being tested: Pyridostigmine, Placebos, non-invasive vagal nerve stimulation
Keywords: Small intestinal bacterial overgrowth, People living with HIV, HIV-associated autonomic neuropathy, Distal symmetric polyneuropathy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

PyridostigmineDrug
Eight weeks of low-dose pyridostigmine
PlacebosDrug
matching placebo x 8 weeks
non-invasive vagal nerve stimulationProcedure or surgery
Also called nVNS
stimulation of the vagus nerve

Study groups in NCT04353778
Study group	Role	What they receive
PLWH	No intervention	People living with HIV (HIV)
Healthy Controls	No intervention	Healthy controls who do not have HIV
Pyridostigmine	Active comparator	PLWH on pyridostigmine 30mg PO TID Receives: Drug: Pyridostigmine
Placebo	Placebo comparator	PLWH on placebo Receives: Drug: Placebos
nVNS	Other	PLWH to undergo non-invasive vagal nerve stimulation Receives: Procedure: non-invasive vagal nerve stimulation

What is being measured

The primary outcome is the main question the study is designed to answer.

Small bowel transit time (SBTT)
Small bowel transit time (SBTT) measured by wireless motility capsule (wmc, smartpill)
Measured: 8 weeks
Gastric pH measurement
Gastric pH measurement measured by wireless motility capsule (wmc, smartpill)
Measured: 8 weeks
Hydrogen/methane breath testing (hbt)
hydrogen/methane breath testing (hbt) to measure small intestinal bacterial overgrowth
Measured: 8 weeks
IL6 measurement [Time Frame: 5 years]
Measured: 8 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

3 Aug 202027 Mar 2026

First posted20 Apr 2020
Study start3 Aug 2020
Primary completion27 Mar 2026
Study completion27 Mar 2026

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (6)Papers the sponsor has linked to this study.
Other trials for HIVStudies of the same condition, open and under way.
More trials run by Icahn School of Medicine at Mount SinaiThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 215 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04353778
Sponsor's protocol ID: GCO 18-2812
Other IDs: 1R01DK122853-01A1
Acronym: EVA
Status last verified: Aug 2026
First submitted: 17 Apr 2020
Last updated: 18 Aug 2026
Results posted: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

Publications

Robinson-Papp J, Nmashie A, Pedowitz E, George MC, Sharma S, Murray J, Benn EKT, Lawrence SA, Machac J, Heiba S, Kim-Schulze S, Navis A, Roland BC, Morgello S. The effect of pyridostigmine on small intestinal bacterial overgrowth (SIBO) and plasma inflammatory biomarkers in HIV-associated autonomic neuropathies. J Neurovirol. 2019 Aug;25(4):551-559. doi: 10.1007/s13365-019-00756-9. Epub 2019 May 16.
PubMed 31098925
Carod-Artal FJ. Infectious diseases causing autonomic dysfunction. Clin Auton Res. 2018 Feb;28(1):67-81. doi: 10.1007/s10286-017-0452-4. Epub 2017 Jul 20.
PubMed 28730326
Robinson-Papp J, Nmashie A, Pedowitz E, Benn EKT, George MC, Sharma S, Murray J, Machac J, Heiba S, Mehandru S, Kim-Schulze S, Navis A, Elicer I, Morgello S. Vagal dysfunction and small intestinal bacterial overgrowth: novel pathways to chronic inflammation in HIV. AIDS. 2018 Jun 1;32(9):1147-1156. doi: 10.1097/QAD.0000000000001802.
PubMed 29596112
Paulon E, Nastou D, Jaboli F, Marin J, Liebler E, Epstein O. Proof of concept: short-term non-invasive cervical vagus nerve stimulation in patients with drug-refractory gastroparesis. Frontline Gastroenterol. 2017 Oct;8(4):325-330. doi: 10.1136/flgastro-2017-100809. Epub 2017 May 24.
PubMed 29067158
Lerman I, Hauger R, Sorkin L, Proudfoot J, Davis B, Huang A, Lam K, Simon B, Baker DG. Noninvasive Transcutaneous Vagus Nerve Stimulation Decreases Whole Blood Culture-Derived Cytokines and Chemokines: A Randomized, Blinded, Healthy Control Pilot Trial. Neuromodulation. 2016 Apr;19(3):283-90. doi: 10.1111/ner.12398. Epub 2016 Mar 15.
PubMed 26990318
Tarn J, Legg S, Mitchell S, Simon B, Ng WF. The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue and Immune Responses in Patients With Primary Sjogren's Syndrome. Neuromodulation. 2019 Jul;22(5):580-585. doi: 10.1111/ner.12879. Epub 2018 Oct 17.
PubMed 30328647

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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