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

18 Years
60 Years
Not Enrolling
Metabolic Syndrome

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Trial Information

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

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.

Inclusion Criteria:

1. 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

2. 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

- Hypertension defined as blood pressure >= 140/90 or on medication

Exclusion Criteria:

1. Age < 18 or > 60 years

2. Body mass index (BMI) < 30 kg/m2

3. Positive tuberculosis (purified protein derivative [PPD]) skin test (5mm induration
or more) on screening

4. Mycobacterial disease treated less than 6 months.

5. 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.

6. Therapy with glucocorticoid or immunosuppressant at time of recruitment or within
past 3 months.

7. Prior or concurrent cyclophosphamide therapy

8. Use of a live vaccine 90 days prior to, or during this study.

9. History of blood dyscrasia including any kind of anemia, thrombocytopenia,
pancytopenia. Women with a reversible cause of anemia that has resolved will be

10. Hemoglobin < 11 g/dl

11. History of malignancy (except patients with surgically cured basal cell or squamous
cell skin cancers who will be eligible)

12. History of organ transplantation

13. HIV-positive status determined by HIV test at screening or known history of any other
immuno-suppressing disease.

14. Hepatitis B or hepatitis C infection detected at screening, lupus (SLE), history of
multiple sclerosis, transverse myelitis, optic neuritis or epilepsy

15. Patients with known autoimmune or inflammatory conditions (excluding patients with
stable, treated hypothyroidism)

16. 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

17. Uncontrolled systolic blood pressure > 150 mmHg or diastolic blood pressure > 100

18. Fasting blood glucose > 126 mg/dL

19. Creatinine > 1.5

20. 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.

21. 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).

22. Positive pregnancy test or lactating females

23. Women of child-bearing potential not currently using non-hormonal birth control
methods including barrier methods (intrauterine device [IUD], condoms, diaphragms) or

24. 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.

25. Subjects who have known hypersensitivity to Enbrel or any of its components or who is
known to have antibodies to etanercept

26. Concurrent sulfasalazine therapy

27. History of recent alcohol or substance abuse (< 1 year)

28. Any condition judged by the patient's physician to cause this clinical trial to be
detrimental to the patient.

29. History of non-compliance with other therapies

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

C-reactive Protein (CRP)

Outcome Description:

As a measure of C-reactive protein (CRP), which is an inflammatory marker, Log10 of the CRP at 6 months is reported

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Steven K Grinspoon

Investigator Role:

Principal Investigator

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

December 2006

Completion Date:

September 2009

Related Keywords:

  • Metabolic Syndrome
  • Inflammation
  • Visceral adiposity
  • TNF
  • Adiponectin
  • glucose tolerance
  • endothelial function
  • metabolic syndrome
  • Metabolic Syndrome X



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