Clincosm LogoSign in Get a demo

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

Sponsor
Icahn School of Medicine at Mount Sinai (Other)
Overall Status
Recruiting
CT.gov ID
NCT04353778
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
250
Enrollment
1
Location
5
Arms
43.9
Anticipated Duration (Months)
5.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

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 Design

Study Type:
Interventional
Anticipated Enrollment :
250 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV
Actual Study Start Date :
Aug 3, 2020
Anticipated Primary Completion Date :
Apr 1, 2024
Anticipated Study Completion Date :
Apr 1, 2024

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Small bowel transit time (SBTT) [5 years]

      Small bowel transit time (SBTT) measured by wireless motility capsule (wmc, smartpill)

    2. Gastric pH measurement [5 years]

      Gastric pH measurement measured by wireless motility capsule (wmc, smartpill)

    3. Hydrogen/methane breath testing (hbt) [5 years]

      hydrogen/methane breath testing (hbt) to measure small intestinal bacterial overgrowth

    4. IL6 measurement. [Time Frame: 5 years] [5 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Icahn School of Medicine at Mount Sinai New York New York United States 10029

    Sponsors and Collaborators

    • Icahn School of Medicine at Mount Sinai
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Jessica Robinson-Papp, Associate Professor, Icahn School of Medicine at Mount Sinai
    ClinicalTrials.gov Identifier:
    NCT04353778
    Other Study ID Numbers:
    • GCO 18-2812
    • 1R01DK122853-01A1
    First Posted:
    Apr 20, 2020
    Last Update Posted:
    Apr 13, 2022
    Last Verified:
    Apr 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Jessica Robinson-Papp, Associate Professor, Icahn School of Medicine at Mount Sinai
    Small intestinal bacterial overgrowth
    People living with HIV
    HIV-associated autonomic neuropathy
    Distal symmetric polyneuropathy
    Additional relevant MeSH terms:
    Pyridostigmine Bromide

    Study Results

    No Results Posted as of Apr 13, 2022