Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV

HIV Clinical Trial

— EVA  

Official title:

Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04353778
• Other study ID #: GCO 18-2812
• Secondary ID: 1R01DK122853-01A
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 3, 2020
• Est. completion date: January 31, 2025

Study information

• Verified date: January 2024
• Source: Icahn School of Medicine at Mount Sinai
• Contact: Alexandra Nmashie, MD
• Phone: 212-241-3193
• Email: Alexandra.nmashie[@]mssm.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: January 31, 2025
• Est. primary completion date: January 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV
• Non-HIV
• Vagus Nerve Dysfunction

Intervention

Drug:
• Pyridostigmine
Eight weeks of low-dose pyridostigmine
• Placebos
matching placebo x 8 weeks

Procedure:
• non-invasive vagal nerve stimulation
stimulation of the vagus nerve

Locations

Country	Name	City	State
United States	Icahn School of Medicine at Mount Sinai	New York	New York

Sponsors (2)

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

Country where clinical trial is conducted

United States, 

References & Publications (6)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

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