Clinical trial NCT02431325: A Study of the Gut Barrier and Blood Vessel Inflammation in Individuals With and Without HIV
Official title: A Study to Investigate Gastrointestinal Epithelial Integrity and Arterial Inflammation in Individuals With and Without HIV
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV
Keywords: HIV
Atherosclerosis
Microbial Translocation
Teduglutide
Gastrointestinal Permeability
Inflammation
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Ragon Institute of MGH, MIT and Harvard
name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Institutes of Health (NIH)
First posted: 2015-05-01
Enrollment: 32
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. Men and women age 21-65 with previously diagnosed HIV disease
2. Stable anti-retroviral therapy (ART) as defined by no changes in ART regimen for \>6 months
3. HIV viral load \< 200 copies/mL
4. To be eligible for colonoscopy procedure, laboratory values that meet the following criteria:

   1. Hemoglobin \> 9.0 g/dL
   2. Absolute neutrophil count ≥ 1000/mm3
   3. Platelet count ≥ 100,000/mm3
   4. Prothrombin time (PT) \< 1.2 x upper limit of normal (ULN)
   5. 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:

1. 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
2. First-degree relative with history of colon cancer
3. Active gall bladder, biliary or pancreatic disease
4. Female subject who is pregnant, nursing or less than 8 weeks post partum.
5. Use of any immunomodulatory agents within 30 days prior to study enrollment
6. History of intolerance, sensitivity, allergy or anaphylaxis to benzodiazepines or other narcotics to be used during the colonoscopy or upper endoscopy procedure
7. 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.
8. Patients with previous allergic reactions to iodine-containing contrast media
9. Renal disease or creatinine \>1.5 mg/dL (contrast will be administered during CT angiography of the heart)
10. History of requiring antibiotic prophylaxis for invasive procedures
11. 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
12. 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
13. 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).
14. 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.
15. Body weight greater than 300 lbs due to CT scanner table limitations
16. Active illicit drug use
17. Patients who report any significant radiation exposure over the course of the year prior to randomization. Significant exposure is defined as:

    1. More than 2 percutaneous coronary interventions (PCI) within 12 months of randomization
    2. More than 2 myocardial perfusion studies within the past 12 months
    3. More than 2 CT angiograms within the past 12 months
    4. Any subjects with history of radiation therapy
18. Patients already scheduled or being considered for a procedure or treatment

    1. requiring significant radiation exposure (e.g., radiation therapy, PCI, or catheter
    2. ablation of arrhythmia) within 12 months of randomization
19. History of malignancy
20. Prior recipient of a HIV vaccine

Primary outcomes:
measure: Change in Arterial Target to Background Ratio of 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Uptake
timeFrame: Change from baseline at 6 months
measure: Change in Intestinal Epithelial Integrity
timeFrame: Change from baseline at 6 months
measure: Change in Soluble CD14 Concentration
timeFrame: Change from baseline at 6 months
Secondary outcomes:
measure: Change in Intestinal CD4+ T-cells
timeFrame: Change from baseline at 6 months
measure: Change in CD14+CD86+CD40+ Monocytes
timeFrame: Change from baseline at 6 months
measure: Change in HLA-DR+CD38+ CD8+ T Cells
timeFrame: Change from baseline at 6 months
measure: Change in HLA-DR+CD38+ CD4+ T Cells
timeFrame: Change from baseline at 6 months
measure: Change in Soluble CD163 Concentration
timeFrame: Change from baseline at 6 months
measure: Change in Intestinal Fatty Acid Binding Protein Concentration
timeFrame: Change from baseline at 6 months
measure: Change in Plasma Riboflavin Concentration
timeFrame: Change from baseline at 6 months
measure: Change in Bone Mineral Density
timeFrame: Change from baseline at 6 months
measure: Change in Plaque Volume on Cardiac Computed Tomography Angiography
timeFrame: Change from baseline at 6 months
measure: Change in Hemoglobin A1c Percentage
timeFrame: Change from baseline at 6 months
measure: Change in Homeostatic Model Assessment-Insulin Resistance (HOMA-IR)
timeFrame: Change from baseline at 6 months
measure: Change in Visceral Adipose Tissue (VAT) Area
timeFrame: Change from baseline at 6 months
measure: Change in Subcutaneous Adipose Tissue (SAT) Area
timeFrame: Change from baseline at 6 months
measure: Change in Body Mass Index (BMI)
timeFrame: Change from baseline at 6 months
measure: Change in Depressive Symptoms
timeFrame: Change from baseline at week 12 and at week 24
measure: Change in Cognitive Performance, Defined as a Global Neurocognitive Z-score
timeFrame: Change from baseline at week 24
measure: Change in Domain-specific Cognitive Performance, Defined as a Domain-specific Neurocognitive Z-score
timeFrame: Change from baseline at week 24
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Janet Lo, MD, MMSc
role: PRINCIPAL_INVESTIGATOR
References: