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Protocol Details

Effects of the Glucocorticoid Antagonist, Mifepristone, on Glucose Intolerance in Obese and Overweight Individuals

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

11-CH-0208

Sponsoring Institute

National Institute of Child Health and Human Development (NICHD)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 35
Max Age: 70

Referral Letter Required

No

Population Exclusion(s)

Children

Special Instructions

Currently Not Provided

Keywords

Metabolism;
Cortisol;
Hypercortisolism

Recruitment Keyword(s)

Glucose Intolerance

Condition(s)

Endocrine Disease;
Diabetes

Investigational Drug(s)

mifepristone and deuterated cortisol@@@cortisol

Investigational Device(s)

None

Intervention(s)

Drug: Mifepristone

Supporting Site

National Institute of Child Health and Human Development

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.

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Eligibility

INCLUSION CRITERIA:

1. Men and women 35 70 years of age

2. Subjects will be overweight or obese, with BMI ranging from 25 - 37 kg/m2.

3. Subjects will have either impaired fasting glucose (greater than or equal to 100 mg/dL) or a 2-hour glucose value greater than or equal to 140 mg/dl during an oral glucose tolerance test (OGTT).

OR

Mild diabetes defined as patients with a Hba1c less than or equal to 7% on no medications (diet-controlled) or on a stable dose of metformin and no other hypoglycemic agents for greater than or equal to 3 months before study entry.

4. Willing and able to comply with study requirements.

EXCLUSION CRITERIA:

1. Pregnancy and lactation

2. Diabetes requiring pharmacologic treatment. Diagnosis of diabetes will be based on the 2011 American Diabetes Association guidelines: Hba1c greater than or equal to 6.5%, fasting plasma glucose greater than or equal to 126 mg/dl, 2-hour glucose greater than or equal to 200 mg/dl during an OGTT, or a random blood glucose greater than or equal to 200 mg/dl along with classic symptoms of hyperglycemia (34)

3. Uncontrolled hypertension (blood pressure greater than or equal to 180/110 mmHg)

4. Current unstable medical conditions including clinically significant impaired cardiac function (Stage III and IV Cardiac failure), cardiac ischemia, severe respiratory insufficiency requiring oxygen therapy as assessed on history and/or physical exam

5. Liver function tests (ALT, AST) more than 3-times the upper normal limit

6. Severe renal impairment (creatinine clearance < 30 ml/min)

7. Evidence of human immunodeficiency virus (HIV) based on history and physical examination and/or known positive HIV antibodies

8. Evidence of hepatitis C based on history and physical examination and/or known positive hepatitis C (HCV) antibody

9. History of hemorrhagic disorders or on anticoagulants

10. History of endometrial cancer, endometrial hyperplasia, unexplained vaginal bleeding, or endometrial thickness greater than 6 mm

11. Change in dose of lipid-lowering medications (including HMG Co-A inhibitors , fibrates, niacin, ezetemibe, and over-the-counter fish oil supplements) within one month of study entry and during the study period

12. Current administration of medications known to be strong CYP3A4 inhibitors including ketoconazole, itraconazole, and erythromycin

13. Use of herbal supplements or grapefruit juice within 14 days of study drug initiation

14. Use of medications or dietary supplements that inihibit or induce CYP3A4 activity within 14 days of study drug initiation

15. Use of oral, injectable, or inhaled glucocorticoids or megestrol in the past six months

16. Use of estrogen-containing hormone therapy

17. Potential pseudocushing s states: depression or intake of > 2 alcoholic drinks a day. Subjects will be screened for depression using the well-validated physician health questionnaire-9 (PHQ-9) with a score cut-off of greater than or equal to 10 for moderate depression (35).

18. Subjects who are actively dieting or are in a weight loss program

19. Midnight salivary cortisol > 100 ng/dl on two separate occasions

20. Untreated thyroid dysfunction (TSH and Free T4 not within normal range). If abnormal on screening labs, they will be repeated to confirm that not due to lab error or non-thyroidal illness.

21. Moderate to severe anemia (hemoglobin < 10 g/dl)

22. Blood donation of more than 500 ml within one month prior to study enrollment

23. Subjects with a prolonged QTc interval on electrocardiogram

24. Unable to give informed consent


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Citations:

Pivonello R, Faggiano A, Lombardi G, Colao A. The metabolic syndrome and cardiovascular risk in Cushing's syndrome. Endocrinol Metab Clin North Am. 2005 Jun;34(2):327-39, viii.

Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009 Aug;94(8):2692-701. Epub 2009 May 26.

Pasquali R, Vicennati V, Cacciari M, Pagotto U. The hypothalamic-pituitary-adrenal axis activity in obesity and the metabolic syndrome. Ann N Y Acad Sci. 2006 Nov;1083:111-28.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Lynnette K. Nieman, M.D.
National Institute of Child Health and Human Development (NICHD)
BG 10-CRC RM 1-3140
10 CENTER DR
BETHESDA MD 20814
(301) 496-8935
niemanl@mail.nih.gov

Lynnette K. Nieman, M.D.
National Institute of Child Health and Human Development (NICHD)
BG 10-CRC RM 1-3140
10 CENTER DR
BETHESDA MD 20814
(301) 496-8935
niemanl@mail.nih.gov

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

prpl@mail.cc.nih.gov

Clinical Trials Number:

NCT01419535

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