Mifepristone Effects on Glucose Intolerance in Obese/Overweight Adults
Condition: Endocrine Disease; Diabetes
MeSH terms: Overweight; Glucose Intolerance; Endocrine System Diseases
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

        -  Metabolic syndrome is a name given to a group of factors that tend to occur together.
           These risk factors include central obesity (extra weight around the middle of the body)
           and high blood pressure and blood sugar levels. They also include low levels of HDL
           ("good cholesterol") and high triglyceride levels. A person is said to have metabolic
           syndrome if they have three or more of the above risk factors. People with metabolic
           syndrome are at increased risk for type 2 diabetes, stroke, and heart disease.

        -  Cortisol, a hormone produced by the adrenal glands, is an important regulator of
           metabolism. People with central obesity and metabolic syndrome may have higher than
           normal cortisol levels that the body cannot regulate properly. Abnormal cortisol levels
           may play an important role in metabolic syndrome. Mifepristone is a drug that blocks
           cortisol. Researchers are interested in studying its effects on metabolic syndrome.

      Objectives:

      - To study the effects of short-term mifepristone treatment for metabolic syndrome.

      Eligibility:

      - Men and Women between 35 and 70 years of age are overweight or obese, and have abnormal
      glucose and triglyceride levels.

      Design:

        -  Participants will be screened with a physical exam and medical history. They will also
           have blood and urine tests.

        -  Participants will be admitted to the metabolic unit at the National Institutes of Health
           Clinical Center for the first 3 days of the study:

        -  Day 1: Body measurements (height, weight, waist, hip, and neck) and blood pressure
           tests. Also, 24 hours of regular blood draws and 24-hour urine collection to monitor
           regular daily cortisol levels.

        -  Day 2: Glucose/insulin infusion test to measure blood sugar levels.

        -  Day 3: Infusion of cortisol-like compounds and then regular blood draws for about 3
           hours to evaluate how cortisol is metabolized.

        -  At the end of Day 3, participants will receive mifepristone or a look-alike capsule to
           take for 7 days at home.

        -  After 7 days, participants will return to the metabolic unit to repeat the Day 1 and Day
           2 study procedures. They will continue to take mifepristone.

        -  One week after the second set of study tests, participants will return for a brief
           physical exam and blood tests.

        -  The study procedures will be repeated after 6 to 8 weeks, with the other study drug.
    

Detailed description: 
      The hormone cortisol is a key regulator of metabolism that influences the use of glucose
      (sugar) and fat as fuels. Persistently increased cortisol levels, as in Cushing s syndrome,
      lead to obesity, type 2 diabetes mellitus and lipid abnormalities including elevated
      triglyceride levels and low high-density lipoprotein (HDL) levels. These same disorders are
      also present in patients without Cushing s syndrome, suggesting that cortisol may be involved
      in their pathogenesis. Mifepristone is a cortisol-like drug that blocks cortisol action in
      the body. It can reverse lipid abnormalities, diabetes and obesity in Cushing s syndrome
      patients but its effects on these conditions have not been tested in patients without the
      syndrome.

      The long-term aim of this clinical trial is to evaluate the ability of mifepristone to
      reverse or improve glucose intolerance, dyslipidemia, hypertension and weight gain. An
      initial 7-day prospective, randomized, placebo-controlled, crossover study is proposed here
      to look at the effect of short-term administration of oral mifepristone or placebo on glucose
      intolerance. Given that there are no human data available on the effect of mifepristone on
      insulin sensitivity, this will be a pilot study of 15 subjects. Data from this study will
      then be used to design a larger trial to evaluate long-term effects on blood pressure and
      weight, as well as glucose and triglyceride control.

      Overweight or obese subjects with abnormal glucose tolerance will undergo each of the two
      treatments in a randomized order, including mifepristone by mouth and a look-alike inert
      tablet by mouth. Each treatment study will include two or three days of baseline tests that
      will be repeated after seven days of treatment. Treatments will be separated by at least six
      and no more than eight weeks. The tests will include blood drawing, urine collection,
      administration of glucose and insulin by vein, and a cortisol-like material to evaluate the
      metabolism of cortisol and a related hormone, corticosterone.
    

Intervention name(s): Mifepristone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Mifepristone 50mg tablet by mouth every six hours for nine days.; Placebo (matching mifepristone 50mg tablet) by mouth every six hours for nine days.
Other intervention name(s): 55245; 11β-[p-(Dimethylamino)phenyl]-17α-(1-propynyl)estra-4,9-dien-17β-ol-3-one; inert look-alike tablet
Intervention MeSH terms: Mifepristone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Metabolism; Cortisol; Hypercortisolism; Glucose Intolerance