Study of TNF-Antagonism in the Metabolic Syndrome (II)

Study Overview
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Brief Summary
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This study will investigate whether etanercept will result in improved inflammatory indices, glucose tolerance and endothelial function in patients with the metabolic syndrome.

Detailed Description
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Metabolic syndrome is an increasingly prevalent disorder associated with elevated risks of type II DM (diabetes mellitus) and cardiovascular morbidity and mortality. A subclinical inflammatory state is thought to contribute to the pathophysiology of metabolic syndrome, insulin resistance, and coronary artery disease (CAD). Tumor Necrosis Factor (TNF) -alpha is an inflammatory cytokine that is increased in a spectrum of inflammatory diseases as well as in insulin resistance. TNF-alpha antagonists are clinically effective in the inflammation of arthritides, and have recently been shown by our group to decrease inflammatory cardiovascular risk markers in metabolic syndrome. Data suggests that adiponectin, a recently discovered adipocytokine that may protect against the development of insulin resistance and atherosclerosis, may be downregulated by TNF-alpha. In addition, population based studies have shown that those with the highest levels of TNF-alpha have an increased relative risk of cardiovascular morbidity while rheumatoid arthritis patients treated with TNF-alpha blockade appear protected from cardiovascular disease. We will perform a 6-month study in which we will administer etanercept, a TNF-alpha receptor fusion protein, to subjects with metabolic syndrome to investigate its effect on surrogate markers of cardiovascular disease, including inflammatory markers, adiponectin and glucose tolerance and endothelial function. The results of the proposed study will have broad implications regarding the physiological role of TNF-alpha on the inflammatory cascade, cardiovascular indices and endothelial function.

Official Title
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Effects of Etanercept in Patients With the Metabolic Syndrome (II)

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Drug: Etanercept
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hyperinsulinemia in the upper quartile of the non-diabetic population defined as >= 10 mU/mL (based on Framingham Data, oral communication, James Meigs, MD) or fasting glucose 110-126 mg/dL Plus two of the following: Abdominal obesity defined by waist hip ratio > 0.90 for men and > 0.85 for women and BMI > 30 kg/m2 Dyslipidemia including serum triglycerides >= 150 mg/dl or serum high density lipoprotein (HDL) < 0.9 mmol/L for men (35 mg/dL) and < 1.0 mmol/L (39mg/dL) for women Hypertension defined as blood pressure >= 140/90 or on medication Exclusion Criteria: Age < 18 or > 60 years Body mass index (BMI) < 30 kg/m2 Positive tuberculosis (purified protein derivative [PPD]) skin test (5mm induration or more) on screening Mycobacterial disease treated less than 6 months. Current or recurrent infection or any underlying condition that may predispose to infection or anyone who has been admitted to the hospital due to bacteremia, pneumonia or any other serious infection. Therapy with glucocorticoid or immunosuppressant at time of recruitment or within past 3 months. Prior or concurrent cyclophosphamide therapy Use of a live vaccine 90 days prior to, or during this study. History of blood dyscrasia including any kind of anemia, thrombocytopenia, pancytopenia. Women with a reversible cause of anemia that has resolved will be eligible. Hemoglobin < 11 g/dl History of malignancy (except patients with surgically cured basal cell or squamous cell skin cancers who will be eligible) History of organ transplantation HIV-positive status determined by HIV test at screening or known history of any other immuno-suppressing disease. Hepatitis B or hepatitis C infection detected at screening, lupus (SLE), history of multiple sclerosis, transverse myelitis, optic neuritis or epilepsy Patients with known autoimmune or inflammatory conditions (excluding patients with stable, treated hypothyroidism) Severe comorbidities (diabetes mellitus requiring insulin, congestive heart failure (CHF) (EF<50% at baseline will be exclusionary) of any severity, myocardial infarction (MI), cerebral vascular accident (CVA) or transient ischemic attack (TIA) within 3 months of screening visit, unstable angina pectoris, oxygen-dependent severe pulmonary disease Uncontrolled systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg Fasting blood glucose > 126 mg/dL Creatinine > 1.5 Current use of insulin, any oral anti-hyperglycemic agents (including insulin sensitizing agents). Initiation of insulin, oral hypoglycemics, or insulin sensitizing agents during the study will result in discontinuation from the study. Initiation of statins, niacin, antihypertensive or fibrate therapy within 6 weeks of the study. Chronic use of fibrates, niacin, or antihypertensives for > 6 weeks prior to study initiation at a stable dose is not exclusionary, but chronic use of statins for > 6 months is exclusionary. Initiation of statins, fibrates, niacin or antihypertensive treatments during the study is not exclusionary but will be considered in the analysis (see Protection against risks). Positive pregnancy test or lactating females Women of child-bearing potential not currently using non-hormonal birth control methods including barrier methods (intrauterine device [IUD], condoms, diaphragms) or abstinence Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit. Subjects who have known hypersensitivity to Enbrel or any of its components or who is known to have antibodies to etanercept Concurrent sulfasalazine therapy History of recent alcohol or substance abuse (< 1 year) Any condition judged by the patient's physician to cause this clinical trial to be detrimental to the patient. History of non-compliance with other therapies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 50 mg one syringe sc 2x per week for three months followed by 50 mg one syringe sc 1X per week for three months<br>|
| Active Comparator: Etanercept<br> | Drug: Etanercept<br>* 50 mg one syringe sc 2X per week for three months followed by 50 mg one syringe sc 1X per week for three months<br>* Other names: Enbrel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-reactive Protein (CRP) | As a measure of C-reactive protein (CRP), which is an inflammatory marker, Log10 of the CRP at 6 months is reported | 6 months | 
| Interleukin-6 (IL-6) | 6 month value of IL-6 (pg/mL) | 6 months | 
| Adiponectin | The ratio of circulating high molecular weight (HMW) adiponectin to total adiponectin ratio (HMW:total Adiponectin) at 6 months is reported. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose Tolerance | Fasting glucose (mg/dL) at 6mo | 6 months | 
| Endothelial Function | Reactive Hyperemia Index (RHI) using peripheral artery tonometry (using Endo-PAT 2000). Peripheral artery tonometry measures blood flow in the tip of the index finger at baseline and in response to vaso-occlusion (inflated blood pressure cuff). The reactive hyperemia index is an index of vasodilation after occlusion compared to baseline. A higher value indicates better vasoreactivity. As this is a relatively new test, there are no thoroughly validated clinically utilized norms. | 6 months | 
| White Blood Cell (WBC) Count | Change in WBC during study (WBC at six months minus WBC at baseline) | Baseline to 6 months | 
| Cardiac Echo Ejection Fraction (EF) | change in EF (6mo - baseline). Please note that the value given is the absolute change in EF (which has units of percent), not the percent change in the variable. | Baseline to 6 months | 
| Body Composition | 6 month visceral adipose tissue (cm^2) - cross-sectional area of the visceral adipose tissue at the level of the 4th lumbar vertebrae was measured using single-slice abdominal computed tomography (CT) scan | 6 months | 
| Tumor Necrosis Factor (TNF) Receptor | Circulating concentrations of Tumor necrosis factor receptor 2 (TNFR2) at 6 months | 6 months | 
| Other Adipocytokines | circulating resistin at 6 months | 6 months | 
| Lipid Levels | total cholesterol (mg/dL) at 6 months | 6 months | 
| Adipocyte Messenger Ribonucleic Acid (mRNA) Levels of Adipocytokines Including Tumor Necrosis Factor (TNF) -Alpha | fold-change in subcutaneous adipose tissue expression of TNF-alpha (mRNA) after 6 months | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNF, Inflammation, Visceral adiposity, Adiponectin, glucose tolerance, endothelial function, metabolic syndrome