Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV (EVA)

January 31, 2024 updated by: Jessica Robinson-Papp, Icahn School of Medicine at Mount Sinai
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

150

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10029
        • Recruiting
        • Icahn School of Medicine at Mount Sinai
        • Contact:
        • Contact:
        • Principal Investigator:
          • Jessica Robinson- Papp, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria :

  • 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
  • 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)

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: PLWH
People living with HIV (HIV)
No Intervention: Healthy Controls
Healthy controls who do not have HIV
Active Comparator: Pyridostigmine
PLWH on pyridostigmine 30mg PO TID
Drug: Pyridostigmine
Eight weeks of low-dose pyridostigmine
Placebo Comparator: Placebo
PLWH on placebo
Drug: Placebos
matching placebo x 8 weeks
Other: nVNS
PLWH to undergo non-invasive vagal nerve stimulation
Procedure: non-invasive vagal nerve stimulation
stimulation of the vagus nerve
Other Names:
  • nVNS

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Icahn School of Medicine at Mount Sinai

Collaborators

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

Investigators

  • Principal Investigator: Jessica Robinson-Papp, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 3, 2020

Primary Completion (Estimated)

January 31, 2025

Study Completion (Estimated)

January 31, 2025

Study Registration Dates

First Submitted

April 17, 2020

First Submitted That Met QC Criteria

April 17, 2020

First Posted (Actual)

April 20, 2020

Study Record Updates

Last Update Posted (Actual)

February 2, 2024

Last Update Submitted That Met QC Criteria

January 31, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GCO 18-2812
  • 1R01DK122853-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

IPD Sharing Time Frame

Beginning 3 months and ending 5 years following article publication.

IPD Sharing Access Criteria

Anyone who wishes to access the data. Data will be published.

IPD Sharing Supporting Information Type

  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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