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AzTrials

HIV DiseaseEarly Phase 1ANGINCT02850276

Autonomic Neuropathy, GI Motility, and Inflammation in HIV

A Early Phase 1 study testing Pyridostigmine in people with HIV Disease, 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

The purpose of this study is to explore a possible link between the autonomic nervous system and immune function in patients with HIV. Sometimes HIV can cause these nerves to function abnormally, this is called HIV-associated autonomic neuropathy (HIV-AN). HIV-AN is a condition that is different from person to person. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
HIV Disease
What is being tested?
Pyridostigmine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
76 participants
Where
1 siteUnited States
Study dates
Nov 2015to 1 Jun 2018
Phase
Early Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

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
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥18 years old
  • Documented evidence of HIV-1 infection
  • Stable CART therapy for ≥3 months Most recent HIV-1 viral load ≤100 copies/ml (value must be within the past six months)
  • English speaking
  • Able to tolerate autonomic testing (e.g. able to stand, able to perform Valsalva maneuver).
  • If using nicotine-containing products willing to refrain from use for 24 hours prior to all testing procedures (autonomic reflex screen, breath testing, and gastric emptying)
  • ≥1 GI symptom on the Survey of Autonomic Symptoms (SAS)47

Who cannot join

  • Diagnosis known to cause autonomic dysfunction other than HIV (e.g. Parkinson's disease, diabetes)
  • Diagnosis known to cause GI dysfunction other than HIV (e.g. peptic ulcer disease, infectious diarrhea)
  • Current use of any of the following classes of medications (due to potential for significant autonomic or GI effects, interaction with pyridostigmine, or interference with one or more of the testing procedures) Prokinetics (e.g. metoclopramide) Anti-diarrheals (e.g. loperamide) Antibiotics Mefloquine
  • Medical or psychiatric conditions precluding safe participation in study procedures or deemed likely to result in hospitalization during the study period.
  • The presence of one or more of the following diagnoses which render the Valsalva maneuver relatively or absolutely contraindicated: uncontrolled glaucoma, aortic stenosis, myocardial infarction in the last 6 months, other retinopathy or unclipped cerebral aneurysm.
  • The presence of one or more of the following diagnoses which impede interpretation of autonomic testing: cardiac arrhythmias or pacemakers.
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  • An allergy to eggs (contraindication to gastric emptying scintigraphy)
  • Any of the following laboratory results:
  • Positive pregnancy test (administered to women of childbearing potential only) Urine toxicology screen positive for stimulants (e.g. amphetamines, cocaine) or opiates/opioids.

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

Official title: Autonomic Neuropathy, Gastrointestinal Motility, and Inflammation in HIV

The purpose of this study is to explore a possible link between the autonomic nervous system and immune function in patients with HIV. Sometimes HIV can cause these nerves to function abnormally, this is called HIV-associated autonomic neuropathy (HIV-AN). HIV-AN is a condition that is different from person to person. In some people it causes no symptoms and is not harmful, in others it may cause symptoms such as dizziness or lightheadedness, nausea, vomiting, diarrhea, constipation, or problems urinating. Most people with HIV-AN don't know that they have it. One of the important nerves in the autonomic nervous system is the vagus nerve. Abnormal function of the vagus nerve may cause stomach and intestinal slowing, which could lead to an overgrowth of bacteria. The body senses these bacteria and tries to fight them, leading to inflammation.

In this study the researchers will test whether abnormal function of the vagus nerve in HIV is associated with stomach slowing and overgrowth of bacteria, and if a drug called pyridostigmine can help.

Read the detailed description

HIV-infected patients commonly develop autonomic neuropathy (HIV-AN), which is a heterogeneous disorder characterized by varying degrees of both sympathetic and vagal dysfunction. We hypothesize that the vagal component of HIV-AN contributes to chronic inflammation, both directly via loss of cholinergic activity, and indirectly via effects on the GI tract, and that these effects will be treatable using the acetylcholinesterase inhibitor pyridostigmine. The autonomic nervous system controls the inflammatory response to lipopolysaccharide (LPS) via the cholinergic anti-inflammatory pathway. This pathway is mediated by the vagus nerve, and is therefore likely impaired in HIV-AN with vagal dysfunction. Vagal dysfunction also causes slowed GI transit, which could exacerbate LPS-driven inflammation by promoting bacterial overgrowth. However, the anti-inflammatory impact of cholinergic pathways is almost completely unstudied in HIV, despite the known importance of inflammation in HIV disease progression. Therefore, in this exploratory pilot, we seek to establish associations between vagal dysfunction, GI motility and inflammation in virally suppressed, CART-treated individuals with HIV-AN.

Specific Aim 1: To determine whether vagal dysfunction is associated with immune activation in CART-treated participants with HIV-AN, and if so to estimate the extent to which this association is mediated by GI effects (i.e. slowed motility, bacterial overgrowth, microbial translocation) versus direct effects of vagal dysfunction.

Specific Aim 2: In a subset of participants who have both vagal and GI dysfunction, to investigate whether 8 weeks of pyridostigmine: a) reduces immune activation, and b) improves GI motility; and if the immune effect depends on the GI effect.

To achieve these aims, participants with HIV-AN and GI symptoms will be assessed for: vagal dysfunction (heart rate variability); GI dysmotility (gastric emptying scintigraphy); small intestinal bacterial overgrowth (breath testing); microbial translocation (LPS and sCD14); and immune activation (IL-6 and CRP). Participants meeting threshold criteria for both vagal and GI dysfunction will then be treated with pyridostigmine for 8 weeks, after which GI and immune measures will be reassessed.

Objectives Specific Aim 1: To determine whether vagal dysfunction is associated with immune activation in HIV-infected participants treated with combination antiretroviral therapy (CART), and if so to estimate the extent to which this association is mediated by GI effects (i.e. slowed motility, bacterial overgrowth, microbial translocation) versus direct effects of vagal dysfunction.

Specific Aim 2: In a subset of participants who have both vagal and GI dysfunction, to investigate whether 8 weeks of pyridostigmine: a) reduces immune activation, and b) improves GI motility; and if both effects are present to determine whether the immune effect depends on the GI effect.

Conditions
HIV Disease
Being tested
Pyridostigmine
Keywords
HIV disease, gastrointestinal problems
Medical subject headings
Acquired Immunodeficiency Syndrome

What participants receive

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

  • PyridostigmineDrug

    Also called Pyridostigmine Bromide, Mestinon, Regonol, Gravitor

Study groups in NCT02850276
Study groupRoleWhat they receive
PyridostigmineExperimental30mg PO three times a day
Receives: Drug: Pyridostigmine

What is being measured

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

  1. Change in Breath Test

    Breath Test at week 8 as compared to baseline. Breath test results is the rise in the combined hydrogen and methane during the breath test.

    Measured: baseline and week 8

  2. Number of Participants With Reduction in Small Intestinal Bacterial Overgrowth (SIBO)

    Number of participants with reduction in Small intestinal bacterial overgrowth (SIBO) assessed with breath testing after 8 weeks of treatment.

    The hydrogen breath test for the detection of small intestinal bacterial overgrowth (SIBO), obtained by having participants exhale into a plastic bag. the hydrogen content of the samples is measured using a commercially available analyzer.

    Measured: week 8

Secondary outcomes (6)
  1. Mean Percent Retention of Gastric Contents on Gastric Emptying Study

    Percent retention of gastric contents on gastric emptying study. GI dysmotility calculated from gastric emptying scintigraphy - measurement of the percent retention of gastric contents at 4 hours.

    Measured: Baseline and week 8

  2. Change in sCD14 Level

    Change in sCD14 level at week 8 as compared to baseline. sCD14 is a marker of macrophage activation commonly used as an indirect measure of translocation

    Measured: Baseline and week 8

  3. Change in TNFα Level

    TNFα is a pro-inflammatory cytokine which is induced by components of translocating bacteria. Change in TNFα level at week 8 compared to baseline

    Measured: Baseline and week 8

  4. Change in IL-6 Plasma Level

    Change in IL-6 plasma level at week 8 as compared to baseline. Plasma interleukin-6 (IL-6), an important inflammatory mediator which predicts mortality in HIV as well as multiple medical co-morbidities, presumably via inflammatory mechanisms.

    Measured: Baseline and week 8

  5. The Composite Autonomic Symptom Score (COMPASS)

    The gastrointestinal domain domain score of the COMPASS contains 12 items which reflect gastrointestinal symptoms of autonomic function. It is scored on a total scale of 0-28, with higher numbers reflecting worse symptoms.

    Measured: Baseline and week 8

  6. Medical Outcomes Study Questionnaire

    Medical Outcomes Study (MOS-HIV) quality of life questionnaire. It is a 35 item questionnaire covering 11 dimensions of health including physical functioning, role functioning, pain, social functioning, emotional well-being, energy/fatigue, cognitive functioning, general health, health distress, overall QOL, and health transition. The total scale ranges from 0-100 with a higher score representing better functioning and well-being.

    Measured: Baseline and week 8

Timeline

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

  1. First posted29 Jul 2016 (estimated)
  2. Study startNov 2015
  3. Primary completion1 Jun 2018
  4. Study completion1 Jun 2018

Resources

More details

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

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
76 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02850276
Sponsor's protocol ID
GCO 14-1454
Other IDs
1R21DK105917-01A1
Acronym
ANGI
Status last verified
May 2019
First submitted
27 Jul 2016
Last updated
29 May 2019
Data monitoring committee
Yes
Individual data sharing
Yes: Data will be shared with participants in real time if the tests have any clinical significance.

Publications

  • Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health during chronic HIV infection. Immunity. 2013 Oct 17;39(4):633-45. doi: 10.1016/j.immuni.2013.10.001.

    PubMed 24138880
  • Marchetti G, Cozzi-Lepri A, Merlini E, Bellistri GM, Castagna A, Galli M, Verucchi G, Antinori A, Costantini A, Giacometti A, di Caro A, D'arminio Monforte A; ICONA Foundation Study Group. Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count. AIDS. 2011 Jul 17;25(11):1385-94. doi: 10.1097/QAD.0b013e3283471d10.

    PubMed 21505312
  • Robinson-Papp J, Sharma S, Simpson DM, Morgello S. Autonomic dysfunction is common in HIV and associated with distal symmetric polyneuropathy. J Neurovirol. 2013 Apr;19(2):172-80. doi: 10.1007/s13365-013-0160-3. Epub 2013 Apr 12.

    PubMed 23580249
  • Robinson-Papp J, Sharma SK. Autonomic neuropathy in HIV is unrecognized and associated with medical morbidity. AIDS Patient Care STDS. 2013 Oct;27(10):539-43. doi: 10.1089/apc.2013.0188. Epub 2013 Sep 13.

    PubMed 24032624
  • George NS, Sankineni A, Parkman HP. Small intestinal bacterial overgrowth in gastroparesis. Dig Dis Sci. 2014 Mar;59(3):645-52. doi: 10.1007/s10620-012-2426-7. Epub 2012 Oct 5.

    PubMed 23053897

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Pyridostigmine in people with HIV Disease, run by Icahn School of Medicine at Mount Sinai at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 May 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Breath Test (time frame: baseline and week 8). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02850276, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2019.

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