Effects of Tumor Necrosis Factor (TNF)-Alpha Antagonism in Patients With Metabolic Syndrome
Condition: Metabolic Syndrome X
MeSH terms: Metabolic Syndrome; Syndrome; Necrosis
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Metabolic syndrome is associated with increased inflammatory cytokines and reduced
      adiponectin, that may be mediated in part by TNF production from abdominal fat. We reasoned
      that an anti-TNF agent would reduce C-reactive protein (CRP) and increase adiponectin,
      improving the inflammatory milieu associated with metabolic syndrome.
    

Detailed description: 
      Screening visit 1:

      Fifty six patients will be randomized to receive etanercept or identical placebo. During the
      screening visit, after informed consent is obtained, subjects will undergo a medical history
      and physical exam, which will include vital signs, weight, abdominal girth measurements and
      an evaluation for signs of underlying infection. A purified protein derivative (PPD) of 5
      tuberculin units (TU) (0.1 milliliter of 5 TU/0.1 ml solution) will be intradermally placed
      to test for the presence of tuberculosis (TB). Fasting blood work will include a complete
      blood count (CBC), glucose, insulin, a cholesterol panel, and urine pregnancy test. Subjects
      will be shown what a subcutaneous injection entails using placebo. Patients will be selected
      based on their laboratory results, abdominal girth measurements and PPD negativity 48 hrs
      after placement.

      Screening visit 2:

      Subjects will return 48 hours after their first screening visit for evaluation of their PPD
      test. In the event of a positive PPD, subjects will be excluded from the study, and their
      primary care physicians will be notified of their test result.

      Day 1 visit:

      Subjects will report to Massachusetts General Hospital (MGH) or Massachusetts Institute of
      Technology (MIT) Clinical Research Center (GCRC) after an overnight fast. Fasting blood work
      will be obtained to test for CRP, adiponectin, IL-6, TNF-alpha, TNF-alpha receptor 1,
      TNF-alpha receptor 2, free fatty acids, glucose, insulin and a cholesterol panel, and CBC. A
      urine pregnancy test will be done. Patients will be asked to recall the food they consumed
      over the past 24 hours. A bionutritionist will measure height, weight, waist, hip, chest,
      arm, neck and thigh circumference. Subjects will be instructed to practice adequate birth
      control throughout the study. Serum will be stored for etanercept antibody testing.

      Subjects will then undergo an insulin modified frequently sampled intravenous (IV) glucose
      tolerance test (FSIGT) as initially developed by Bergman et al.

      Dual energy x-ray absorptiometry (DEXA) (Hologic QDR 4500) will be used to determine whole
      body and regional fat. The technique has a precision error (1 SD) of 3% for whole body fat
      and 1.5% for lean mass. Subjects will also undergo a single thin-slice CT scan of the abdomen
      at L4 vertebral body to determine visceral and subcutaneous fat area.

      Indirect calorimetry for the measurement of resting energy expenditure indirect calorimetry
      using the Deltatrac instrument (Sensormedics, Anaheim, CA) will be carried out.

      Drug administration:

      Patients will be given a total of either etanercept 50 mg subcutaneously or placebo
      subcutaneously at the GCRC at the end of their visit. They will receive this in two
      injections of 25 mg each, one given immediately following the other, at different body sites.
      Etanercept will be supplied as a sterile, white, preservative-free, lyophilized powder. The
      pharmacy will reconstitute it with 1 mL of the supplied sterile bacteriostatic water for
      injection (BWFI), United States Pharmacopeia (USP) (containing 0.9% benzyl alcohol). Each
      vial of etanercept contains 25 mg etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg
      tromethamine. Subjects will receive the 50 mg dose of etanercept or placebo once a week,
      given as two 25 mg injections, one immediately following the other, at different body sites,
      at each of their ensuing three visits to the GCRC, on Visit Day 8, Visit Day 15 and Visit Day
      22. Subjects will be monitored for 30 minutes after the injection of study drug at each
      visit. The skin injection site will be observed and their vital signs will be taken. If a
      subject has a significant exposure to varicella virus during the study, transient termination
      of the study will be considered.

      Day 8 visit, Day 15 visit, Day 22 visit:

      Subjects will report to MGH or MIT Clinical Research Center after an overnight fast. Each
      subject will undergo a history and physical exam to assess for safety and compliance. Fasting
      blood work will be obtained. A bionutritionist will measure subjects' height, weight, hip and
      waist circumference and calculate a waist to hip ratio. They will receive 50 mg of either
      etanercept or placebo, given as two 25 mg doses subcutaneously, at different body sites.

      Day 25 visit:

      Subjects will report to MGH or MIT Clinical Research Center after an overnight fast. Each
      subject will undergo a history and physical exam to assess for safety and compliance. Blood
      work, a urine pregnancy test and 24 hour food recall will be collected, identical to that on
      Day 1 visit. Anthropomorphic measurements will be the same as the Day 1 visit. Subjects will
      undergo an intravenous glucose tolerance test (IVGTT) identical to that on the Day 1 visit.
      Subjects will undergo a DEXA, bioelectric impedance analysis (BIA), and CT, and indirect
      calorimetry identical to those on the Day 1 visit. No study drug will be administered at this
      visit.
    

Intervention name(s): Etanercept; Placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Etanercept
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: TNF; metabolic syndrome; inflammation; CRP; adiponectin