Mifepristone for Metabolic Syndrome

Tracking Information
First Submitted Date ICMJE	August 17, 2011
First Posted Date ICMJE	August 18, 2011
Last Update Posted Date	March 29, 2018
Study Start Date ICMJE	August 17, 2011
Actual Primary Completion Date	November 29, 2017 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: April 11, 2012)	To change in insulin sensitivity index based on the effect of insulin on glucose during frequently sampled IV glucose tolerance test (FSIVGTT)
Original Primary Outcome Measures ICMJE; (submitted: August 17, 2011)	Lipid response to mifepristone
Change History	Complete list of historical versions of study NCT01419535 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: August 17, 2011)	Whole-body rate of regenerating cortisol response to mifepristone of glucose insulin sensitivity, free fatty acid clearance, cortisol metabolites, adrenal hormones.
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Mifepristone for Metabolic Syndrome
Official Title ICMJE	Effects of the Glucocorticoid Antagonist, Mifepristone, on Glucose Intolerance in Obese and Overweight Individuals
Brief 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.
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Crossover Assignment; Primary Purpose: Treatment
Condition ICMJE	Endocrine Disease; Diabetes
Intervention ICMJE	Drug: Mifepristone
Study Arms	Not Provided
Publications *	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. Review.; 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. doi: 10.1210/jc.2009-0370. Epub 2009 May 26. Review.; 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. Review.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: November 30, 2017)	63
Original Estimated Enrollment ICMJE; (submitted: August 17, 2011)	40
Actual Study Completion Date	November 29, 2017
Actual Primary Completion Date	November 29, 2017 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	INCLUSION CRITERIA: Men and women 35 - 70 years of age Subjects will be overweight or obese, with BMI ranging from 25 - 37 kg/m2. 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. Willing and able to comply with study requirements. EXCLUSION CRITERIA: Pregnancy and lactation; 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); Uncontrolled hypertension (blood pressure greater than or equal to 180/110 mmHg); 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; Liver function tests (ALT, AST) more than 3-times the upper normal limit; Severe renal impairment (creatinine clearance < 30 ml/min); Evidence of human immunodeficiency virus (HIV) based on history and physical examination and/or known positive HIV antibodies; Evidence of hepatitis C based on history and physical examination and/or known positive hepatitis C (HCV) antibody; History of hemorrhagic disorders or on anticoagulants; History of endometrial cancer, endometrial hyperplasia, unexplained vaginal bleeding, or endometrial thickness greater than 6 mm; 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; Current administration of medications known to be strong CYP3A4 inhibitors including ketoconazole, itraconazole, and erythromycin; Use of herbal supplements or grapefruit juice within 14 days of study drug initiation; Use of medications or dietary supplements that inihibit or induce CYP3A4 activity within 14 days of study drug initiation; Use of oral, injectable, or inhaled glucocorticoids or megestrol in the past six months; Use of estrogen-containing hormone therapy; 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).; Subjects who are actively dieting or are in a weight loss program; Midnight salivary cortisol > 100 ng/dl on two separate occasions; 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.; Moderate to severe anemia (hemoglobin < 10 g/dl); Blood donation of more than 500 ml within one month prior to study enrollment; Subjects with a prolonged QTc interval on electrocardiogram; Unable to give informed consent
Sex/Gender	Sexes Eligible for Study: All
Ages	35 Years to 70 Years (Adult, Senior)
Accepts Healthy Volunteers	Yes
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01419535
Other Study ID Numbers ICMJE	110208; 11-CH-0208
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
Study Sponsor ICMJE	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Lynnette K Nieman, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
PRS Account	National Institutes of Health Clinical Center (CC)
Verification Date	November 29, 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP