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

Sponsor

Massachusetts General Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT02431325

Collaborator

Ragon Institute of MGH, MIT and Harvard (Other), National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Institutes of Health (NIH) (NIH)

Enrollment

Location

Arms

61.7

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
HIV	Drug: Teduglutide Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Dec 1, 2015

Actual Primary Completion Date :

Jan 21, 2020

Actual Study Completion Date :

Jan 21, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Teduglutide Teduglutide, subcutaneous injection, 0.05 mg/kg/day, 6 months duration	Drug: Teduglutide Other Names: Gattex
Placebo Comparator: Placebo Placebo, subcutaneous injection, 6 months duration	Drug: Placebo

Arm

Intervention/Treatment

Experimental: Teduglutide

Teduglutide, subcutaneous injection, 0.05 mg/kg/day, 6 months duration

Drug: Teduglutide

Other Names:

Gattex

Placebo Comparator: Placebo

Placebo, subcutaneous injection, 6 months duration

Drug: Placebo

Outcome Measures

Primary Outcome Measures

Change in soluble CD14 concentration [Change from baseline at 6 months]
Change in intestinal epithelial integrity [Change from baseline at 6 months]
Change in arterial target to background ratio of 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) uptake [Change from baseline at 6 months]

Secondary Outcome Measures

Change in intestinal CD4+ T-cells [Change from baseline at 6 months]
Change in plaque volume on cardiac computed tomography angiography [Change from baseline at 6 months]
Change in hemoglobin A1c percentage [Change from baseline at 6 months]
Change in Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) [Change from baseline at 6 months]
Change in visceral adipose tissue (VAT) area [Change from baseline at 6 months]
Change in subcutaneous adipose tissue (SAT) area [Change from baseline at 6 months]
Change in body mass index (BMI) [Change from baseline at 6 months]
Change in soluble CD163 concentration [Change from baseline at 6 months]
Change in intestinal fatty acid binding protein concentration [Change from baseline at 6 months]
Change in bone mineral density [Change from baseline at 6 months]
Change in depressive symptoms [Change from baseline at week 12 and at week 24]
Change in cognitive performance, defined as a global neurocognitive z-score [Change from baseline at week 24]
Change in domain-specific cognitive performance, defined as a domain-specific neurocognitive z-score [Change from baseline at week 24]

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
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 (Hep-Lock, Hep-Pak), Hep-Pak CVC, Heparin Lock Flush), 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 HPV 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