A Study to Investigate Gastrointestinal Epithelial Integrity and Arterial Inflammation in Individuals With and Without HIV
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Change in Arterial Target to Background Ratio of 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Uptake
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 21 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Teduglutide
Teduglutide, subcutaneous injection, 0.05 mg/kg/day, 6 months duration
干预措施: Teduglutide (Drug)
Placebo
Placebo, subcutaneous injection, 6 months duration
干预措施: Placebo (Drug)
结局指标
主要结局
Change in Arterial Target to Background Ratio of 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Uptake
时间窗: Change from baseline at 6 months
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 in Intestinal Epithelial Integrity
时间窗: Change from baseline at 6 months
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 in Soluble CD14 Concentration
时间窗: Change from baseline at 6 months
Soluble CD14 is a marker of monocyte activation. An increase in soluble CD14 concentration indicates an increase in inflammation.
次要结局
- Change in CD14+CD86+CD40+ Monocytes(Change from baseline at 6 months)
- Change in HLA-DR+CD38+ CD8+ T Cells(Change from baseline at 6 months)
- Change in HLA-DR+CD38+ CD4+ T Cells(Change from baseline at 6 months)
- Change in Soluble CD163 Concentration(Change from baseline at 6 months)
- Change in Intestinal CD4+ T-cells(Change from baseline at 6 months)
- Change in Intestinal Fatty Acid Binding Protein Concentration(Change from baseline at 6 months)
- Change in Plasma Riboflavin Concentration(Change from baseline at 6 months)
- Change in Hemoglobin A1c Percentage(Change from baseline at 6 months)
- Change in Bone Mineral Density(Change from baseline at 6 months)
- Change in Plaque Volume on Cardiac Computed Tomography Angiography(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 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)
研究者
Janet Lo, MD
Assistant Professor in Medicine
Massachusetts General Hospital