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

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ClinicalTrials.gov Identifier: NCT04353778
Recruitment Status : Recruiting
First Posted : April 20, 2020
Last Update Posted : April 13, 2022
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Jessica Robinson-Papp, Icahn School of Medicine at Mount Sinai

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
HIV Non-HIV Vagus Nerve Dysfunction Drug: Pyridostigmine Drug: Placebos Procedure: non-invasive vagal nerve stimulation 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : August 3, 2020
Estimated Primary Completion Date : April 2024
Estimated Study Completion Date : April 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

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

nVNS
PLWH to undergo non-invasive vagal nerve stimulation
Procedure: non-invasive vagal nerve stimulation
stimulation of the vagus nerve
Other Name: nVNS




Primary Outcome Measures :
  1. Small bowel transit time (SBTT) [ Time Frame: 5 years ]
    Small bowel transit time (SBTT) measured by wireless motility capsule (wmc, smartpill)

  2. Gastric pH measurement [ Time Frame: 5 years ]
    Gastric pH measurement measured by wireless motility capsule (wmc, smartpill)

  3. Hydrogen/methane breath testing (hbt) [ Time Frame: 5 years ]
    hydrogen/methane breath testing (hbt) to measure small intestinal bacterial overgrowth

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


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04353778


Contacts
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Contact: Alexandra Nmashie, MD 212-241-3193 Alexandra.nmashie@mssm.edu
Contact: Mary Catherine George, MM, PhD 212-241-0784 mary-catherine.george@mssm.edu

Locations
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United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Alexandra Nmashie, MD    212-241-3193    Alexandra.nmashie@mssm.edu   
Contact: Mary Catherine George, MM,PhD    212-241-0784    mary-catherine.george@mssm.edu   
Principal Investigator: Jessica Robinson- Papp, MD         
Sponsors and Collaborators
Icahn School of Medicine at Mount Sinai
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Jessica Robinson-Papp, MD Icahn School of Medicine at Mount Sinai
Publications:

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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 ( U.S. NIH Grant/Contract )
First Posted: April 20, 2020    Key Record Dates
Last Update Posted: April 13, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Beginning 3 months and ending 5 years following article publication.
Access Criteria: Anyone who wishes to access the data. Data will be published.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jessica Robinson-Papp, 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:
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Pyridostigmine Bromide
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs