A Study of the Gut Barrier and Blood Vessel Inflammation in Individuals With and Without HIV

Study Overview
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Brief Summary
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The purpose of this research study is to determine whether teduglutide can repair a leaky gut, decrease inflammation, and prevent or treat plaque, a build-up of fat and other materials in the blood vessels of the heart, in people with HIV. HIV disease is linked to inflammatory changes and leakiness of the gut. These changes or conditions may increase the risk of developing heart and blood vessel disease. The investigators believe teduglutide can help repair the gut barrier in people with HIV, leading to a decrease in inflammation and plaque in the blood vessels of the heart.

Detailed Description
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As more people with HIV gain access to combination antiretroviral therapy (cART), cardiovascular disease has become increasingly prevalent and a significant cause of mortality. Activation of the innate immune system may stimulate inflammatory mechanisms of atherosclerosis development. Loss of gastrointestinal (GI) mucosal epithelial integrity and loss of CD4+ T-lymphocytes in the intestinal lamina propria occur in HIV-infected patients and are not fully restored by cART. Translocation of microbial products from the intestinal lumen into the systemic circulation has been demonstrated to be increased in HIV-infected patients and the investigators hypothesize that it is a key driver of monocyte and macrophage activation. In turn, these pro-inflammatory monocytes and macrophages can induce atherosclerotic disease development. The purpose of the research study is to determine the effects of a glucagon-like peptide-2 analog, teduglutide, on intestinal epithelial integrity, microbial translocation across the gut lumen, markers of innate immune system activation including the monocyte transcriptome, bone, arterial inflammation, and atherosclerosis in a 6-month randomized, double-blind placebo-controlled proof of concept trial in HIV-infected individuals.

Official Title
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A Study to Investigate Gastrointestinal Epithelial Integrity and Arterial Inflammation in Individuals With and Without HIV

Conditions
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HIV

Intervention / Treatment
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* Drug: Teduglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women age 21-65 with previously diagnosed HIV disease Stable anti-retroviral therapy (ART) as defined by no changes in ART regimen for >6 months HIV viral load < 200 copies/mL To be eligible for colonoscopy procedure, laboratory values that meet the following criteria: Hemoglobin > 9.0 g/dL Absolute neutrophil count ≥ 1000/mm3 Platelet count ≥ 100,000/mm3 Prothrombin time (PT) < 1.2 x upper limit of normal (ULN) Partial thromboplastin time (PTT) < 1.5 x ULN 4. Ability and willingness to give written informed consent and to comply with study requirements Exclusion Criteria: History of clinically significant gastrointestinal disease including but not limited to: colon cancer, intestinal obstruction, ulcerative colitis, Crohn's disease, or history of C. difficile within the past 3 months First-degree relative with history of colon cancer Active gall bladder, biliary or pancreatic disease Female subject who is pregnant, nursing or less than 8 weeks post partum. Use of any immunomodulatory agents within 30 days prior to study enrollment History of intolerance, sensitivity, allergy or anaphylaxis to benzodiazepines or other narcotics to be used during the colonoscopy or upper endoscopy procedure Contraindication to beta-blocker (including moderate to severe asthma or heart block) or nitroglycerin use as these drugs are given as part of the standard cardiac CT protocol. Previous allergic reaction to beta blocker or nitroglycerin. Patients with previous allergic reactions to iodine-containing contrast media Renal disease or creatinine >1.5 mg/dL (contrast will be administered during CT angiography of the heart) History of requiring antibiotic prophylaxis for invasive procedures History of myocardial infarction, decompensated cirrhosis, or any other condition that in the opinion of the investigator will compromise ability to participate in the study Currently taking anticoagulants including but not limited to: heparin, warfarin (Coumadin), tinzaparin (Innohep), enoxaparin (Lovenox), danaparoid (Orgaran), dalteparin (Fragmin), clopidogrel (Plavix), prophylactic aspirin, and regular NSAID use Subject taking any of the following medications: statins, systemic steroids (inhaled or nasal steroid therapy is permitted), interleukins, systemic interferons (e.g. local injection of interferon alpha for treatment of human papilloma virus is permitted), systemic chemotherapy including oral chemotherapeutic agents, methotrexate, octreotide, growth hormone, antiarrhythmics including digoxin, antiepileptics, immunosuppressants, vancomycin, rifampin, aminoglycosides, clonidine, prazosin, lithium and ritonavir-boosted lopinavir (Kaletra). Subject has had two or more endoscopy procedures (sigmoidoscopy, upper endoscopy or colonoscopy) within the past 12 months for clinical purposes or other research studies. Body weight greater than 300 lbs due to CT scanner table limitations Active illicit drug use Patients who report any significant radiation exposure over the course of the year prior to randomization. Significant exposure is defined as: More than 2 percutaneous coronary interventions (PCI) within 12 months of randomization More than 2 myocardial perfusion studies within the past 12 months More than 2 CT angiograms within the past 12 months Any subjects with history of radiation therapy Patients already scheduled or being considered for a procedure or treatment requiring significant radiation exposure (e.g., radiation therapy, PCI, or catheter ablation of arrhythmia) within 12 months of randomization History of malignancy Prior recipient of a HIV vaccine

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Teduglutide<br>Teduglutide, subcutaneous injection, 0.05 mg/kg/day, 6 months duration | Drug: Teduglutide<br> <br> * Other names: Gattex;|
| Placebo Comparator: Placebo<br>Placebo, subcutaneous injection, 6 months duration | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Arterial Target to Background Ratio of 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Uptake | Change in maximum target to background ratio (TBRmax) of the most diseased segment (MDS) of the carotid index vessel. A negative number for the change in TBR implies a reduction in activity over time, which is considered an improvement in carotid arterial inflammation. Arterial FDG Uptake provides a measure of inflammation in the artery wall. TBR is target-to-background ratio (a measure of the ratio of the activity in the vessel wall divided by the blood background). The most diseased segment is the approximately 1-cm section of the vessel with the highest activity at baseline. The results are expressed as the change in the mean value, of the TBR, from baseline to 6 months. | Change from baseline at 6 months | 
| Change in Intestinal Epithelial Integrity | Change in plasma citrulline is calculated as log2 of the ratio of plasma citrulline at study end to baseline. Citrulline is a measure of functional small bowel mass, so a positive number is considered an improvement in intestinal epithelial integrity. | Change from baseline at 6 months | 
| Change in Soluble CD14 Concentration | Soluble CD14 is a marker of monocyte activation. An increase in soluble CD14 concentration indicates an increase in inflammation. | Change from baseline at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Intestinal CD4+ T-cells | Change in CD161+CCR6+ (Th17) cells as a percentage of CD4+ T-cells in the duodenum. An increase in Th17 cells indicates a beneficial restoration of this CD4+ T-cell population in the small intestine, which are pathologically depleted in people with HIV. | Change from baseline at 6 months | 
| Change in CD14+CD86+CD40+ Monocytes | Change in pro-inflammatory monocytes. A positive change indicates increased inflammation. | Change from baseline at 6 months | 
| Change in HLA-DR+CD38+ CD8+ T Cells | Change in activated CD8+ T Cells. A positive change indicates increased inflammation. | Change from baseline at 6 months | 
| Change in HLA-DR+CD38+ CD4+ T Cells | Change in activated CD4+ T Cells. A positive change indicates increased inflammation. | Change from baseline at 6 months | 
| Change in Soluble CD163 Concentration | An increase in soluble CD163 concentration indicates an increase in inflammation. | Change from baseline at 6 months | 
| Change in Intestinal Fatty Acid Binding Protein Concentration | An increase in I-FABP indicates an increase in intestinal mucosal damage. | Change from baseline at 6 months | 
| Change in Plasma Riboflavin Concentration | Change in plasma riboflavin is calculated as log2 of the ratio of plasma riboflavin at study end to baseline. A positive number indicates an increase in riboflavin levels. | Change from baseline at 6 months | 
| Change in Bone Mineral Density | Change in femoral neck bone mineral density. An increase in bone mineral density is beneficial for bone health. | Change from baseline at 6 months | 
| Change in Plaque Volume on Cardiac Computed Tomography Angiography | Noncalcified plaque volume. Increased noncalcified plaque volume may indicate increased atherosclerosis. | Change from baseline at 6 months | 
| Change in Hemoglobin A1c Percentage | A higher hemoglobin A1c percentage indicates a higher blood glucose level over a 3 month average. | Change from baseline at 6 months | 
| Change in Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) | A higher HOMA-IR indicates greater insulin resistance. Values greater than 2 suggests insulin resistance. HOMA-IR was calculated using a formula based on Matthews et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419. | Change from baseline at 6 months | 
| Change in Visceral Adipose Tissue (VAT) Area | Abdominal VAT area was measured using single-slice abdominal CT at the level of the fourth lumbar vertebra. VAT is considered metabolically unhealthy fat. | Change from baseline at 6 months | 
| Change in Subcutaneous Adipose Tissue (SAT) Area | Abdominal SAT area was measured using single-slice abdominal CT at the level of the fourth lumbar vertebra. | Change from baseline at 6 months | 
| Change in Body Mass Index (BMI) | BMI is a measure of adiposity. | Change from baseline at 6 months | 
| Change in Depressive Symptoms | Change in the Center for Epidemiological Studies-Depression (CES-D) score. Scores range from 0 to 60, with high scores indicating greater depressive symptoms. | Change from baseline at week 12 and at week 24 | 
| Change in Cognitive Performance, Defined as a Global Neurocognitive Z-score | The Global Neurocognitive Z-Score is calculated as an average of the z-scores from the following neurocognitive assessments: Hopkins Verbal Learning Test (HVLT) Total Recall, HVLT Delayed Recall, HVLT Retention, HVLT Recognition, Wechsler Adult Intelligence Scale (WAIS) Digit Span Forward, WAIS Digit Span Backward, WAIS Digit Span Sequence, Stroop Word, Stroop Color, Stroop Color Word, Stroop Interference, Grooved Pegboard Dominant, and Grooved Pegboard Nondominant. A z-score of 0 corresponds with the population mean, and a positive z-score indicates better neurocognitive function than the population mean. A positive change indicates an improvement in neurocognitive function, and a negative change indicates a detriment to performance over time. | Change from baseline at week 24 | 
| Change in Domain-specific Cognitive Performance, Defined as a Domain-specific Neurocognitive Z-score | Change in motor-specific performance z-score. A z-score of 0 corresponds with the population mean, and a positive z-score indicates better motor-specific performance than the population mean. A positive change indicates an improvement in motor-specific performance, and a negative change indicates a detriment to performance over time. | Change from baseline at week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Atherosclerosis, Microbial Translocation, Teduglutide, Gastrointestinal Permeability, Inflammation