ANGI: Autonomic Neuropathy, GI Motility, and Inflammation in HIV

• Sponsor: Icahn School of Medicine at Mount Sinai (Other)
• Overall Status: Completed
• CT.gov ID: NCT02850276
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 76
• Location: 1
• Arm: 1
• Duration (Months): 31
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief 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. 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.

Condition or Disease	Intervention/Treatment	Phase
HIV Disease	Drug: Pyridostigmine	Early Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Autonomic Neuropathy, Gastrointestinal Motility, and Inflammation in HIV
• Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: Jun 1, 2018
• Actual Study Completion Date: Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pyridostigmine 30mg PO three times a day	Drug: Pyridostigmine; Other Names: Pyridostigmine Bromide Mestinon Regonol Gravitor

Outcome Measures

Primary Outcome Measures

1. Change in Breath Test [baseline and week 8]

   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.

2. Number of Participants With Reduction in Small Intestinal Bacterial Overgrowth (SIBO) [week 8]

   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.

Secondary Outcome Measures

1. Mean Percent Retention of Gastric Contents on Gastric Emptying Study [Baseline and week 8]

   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.

2. Change in sCD14 Level [Baseline and week 8]

   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

3. Change in TNFα Level [Baseline and week 8]

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

4. Change in IL-6 Plasma Level [Baseline and week 8]

   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.

5. The Composite Autonomic Symptom Score (COMPASS) [Baseline and week 8]

   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.

6. Medical Outcomes Study Questionnaire [Baseline and week 8]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• ≥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

Exclusion Criteria:

• 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.

• 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.

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 Institutes of Health (NIH)
• 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)

• Study Protocol and Statistical Analysis Plan - Jul 1, 2016

More Information

Additional Information:

• Related Info

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.
• 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.
• Marchetti G, Cozzi-Lepri A, Merlini E, Bellistrì 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.
• 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.
• 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.

• Responsible Party: Jessica Robinson-Papp, Associate Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT02850276
• Other Study ID Numbers: GCO 14-1454; 1R21DK105917-01A1
• First Posted: Jul 29, 2016
• Last Update Posted: May 29, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Jessica Robinson-Papp, Associate Professor, Icahn School of Medicine at Mount Sinai: HIV disease; gastrointestinal problems
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Inflammation; Bromides; Pyridostigmine Bromide

Study Results

Participant Flow

Recruitment Details	Enrollment period from November 2015 to Jan 2018

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Period Title: Overall Study
STARTED	76
COMPLETED	15
NOT COMPLETED	61

Baseline Characteristics

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Overall Participants	76
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.9 (6.6)
Sex: Female, Male (Count of Participants)
Female	20 26.3%
Male	56 73.7%
Race/Ethnicity, Customized (Count of Participants)
African-American	39 51.3%
Hispanic/Latino	22 28.9%
White	14 18.4%
Other	1 1.3%
Current CD4+ count (cells/mm^3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm^3]	602
Nadir CD4+ count (cells/mm^3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm^3]	200
Duration of know HIV infection (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	21
Early Satiety GI symptom (Count of Participants)
Count of Participants [Participants]	43 56.6%
Post-prandial bloating GI symptom (Count of Participants)
Count of Participants [Participants]	55 72.4%
Nausea (Count of Participants)
Count of Participants [Participants]	53 69.7%
Post-prandial vomiting (Count of Participants)
Count of Participants [Participants]	15 19.7%
Cramping/colicky abdominal pain (Count of Participants)
Count of Participants [Participants]	41 53.9%
Moderate to severe diarrhea (Count of Participants)
Count of Participants [Participants]	30 39.5%
Moderate to severe constipation (Count of Participants)
Count of Participants [Participants]	31 40.8%
Vagal sub-score >=1 (Count of Participants)
Count of Participants [Participants]	30 39.5%
Adrenal sub-score >=1 (Count of Participants)
Count of Participants [Participants]	55 72.4%
Sudomotor sub-score >=1 (Count of Participants)
Count of Participants [Participants]	63 82.9%
Total CASS >=3 (Count of Participants)
Count of Participants [Participants]	49 64.5%
Autonomic neuropathy CASS vagal subscore >=1 (Count of Participants)
Count of Participants [Participants]	30 39.5%
Autonomic neuropathy BRS-V of <4 (Count of Participants)
Count of Participants [Participants]	33 43.4%
Autonomic neuropathy CASS >=3 (Count of Participants)
Count of Participants [Participants]	49 64.5%

Outcome Measures

1. Primary Outcome

Title	Change in Breath Test
Description	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.
Time Frame	baseline and week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Measure Participants	15
Baseline	28
week 8	14

2. Primary Outcome

Title	Number of Participants With Reduction in Small Intestinal Bacterial Overgrowth (SIBO)
Description	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.
Time Frame	week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Measure Participants	15
Count of Participants [Participants]	13 17.1%

3. Secondary Outcome

Title	Mean Percent Retention of Gastric Contents on Gastric Emptying Study
Description	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.
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day
Measure Participants	15
Baseline	3
week 8	2

4. Secondary Outcome

Title	Change in sCD14 Level
Description	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
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Measure Participants	15
Baseline	2573
Week 8	2095

5. Secondary Outcome

Title	Change in TNFα Level
Description	TNFα is a pro-inflammatory cytokine which is induced by components of translocating bacteria. Change in TNFα level at week 8 compared to baseline
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Measure Participants	15
Baseline	134.0
week 8	117.5

6. Secondary Outcome

Title	Change in IL-6 Plasma Level
Description	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.
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Measure Participants	15
Baseline	30.5
Week 8	26.5

7. Secondary Outcome

Title	The Composite Autonomic Symptom Score (COMPASS)
Description	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.
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Measure Participants	15
Baseline	8 (4)
Week 8	8.6 (4.8)

8. Secondary Outcome

Title	Medical Outcomes Study Questionnaire
Description	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.
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
Measure Participants	15
Baseline	66.1 (6.2)
Week 8	65 (7)

Adverse Events

Time Frame	8 weeks
Arm/Group Title	Pyridostigmine
Arm/Group Description	30mg PO three times a day for 8 weeks
All Cause Mortality
	Pyridostigmine
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Serious Adverse Events
	Pyridostigmine
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Other (Not Including Serious) Adverse Events
	Pyridostigmine
	Affected / at Risk (%)	# Events
Total	5/15 (33.3%)
Gastrointestinal disorders
Stomach Cramps	1/15 (6.7%)
Diarrhea	3/15 (20%)
Flatulence	1/15 (6.7%)
General disorders
Dizziness	1/15 (6.7%)

Limitations/Caveats

Limitations include difficulty with recruitment resulting in small sample size, and lack of placebo control.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.