Mifepristone Effects on Glucose Intolerance in Obese/Overweight Adults

NCT01419535 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 11020811-CH-0208ZIADK075121
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

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.

Conditions

Endocrine Disease; Diabetes

Keywords

Metabolism; Cortisol; Hypercortisolism; Glucose Intolerance

Outcome Measures

Primary Outcomes (1)

• Change in Insulin Sensitivity Index

  insulin sensitivity index based on the effect of insulin on glucose during frequently sampled intravenous glucose tolerance test (FSIVGTT)

  Nine days

Secondary Outcomes (5)

• Change in Fasting Plasma Glucose

  Nine days

• Change in Fasting Insulin Levels

  9 days

• Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)

  9 days

• Adipose-tissue Insulin Resistance Index (Adipo-IR)

  9 days

• Adipose-tissue Insulin Sensitivity Index (Adipo-SI)

  9 days

Study Arms (2)

Mifepristone, then Placebo

EXPERIMENTAL

Participants first received Mifepristone 50mg tablet every six hours for nine days. After a washout period of no fewer than 6 but no more than 8 weeks, they then received Placebo tablet (matching mifepristone 50 mg) every six hours for nine days.

Drug: Mifepristone; Drug: Placebo

Placebo, then Mifepristone

EXPERIMENTAL

Participants first received Placebo tablet (matching mifepristone 50 mg) every six hours for nine days. After a washout period of no fewer than 6 but no more than 8 weeks, they then received Mifepristone 50 mg tablet every six hours for nine days.

Drug: Mifepristone; Drug: Placebo

Interventions

Mifepristone DRUG

Mifepristone 50mg tablet by mouth every six hours for nine days.

Also known as: 55245, 11β-[p-(Dimethylamino)phenyl]-17α-(1-propynyl)estra-4,9-dien-17β-ol-3-one

Mifepristone, then Placebo; Placebo, then Mifepristone

Placebo DRUG

Placebo (matching mifepristone 50mg tablet) by mouth every six hours for nine days.

Also known as: inert look-alike tablet

Mifepristone, then Placebo; Placebo, then Mifepristone

Eligibility Criteria

• Age: 35 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women 35 - 70 years of age
• Subjects will be overweight or obese, with body mass index (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).
• Mild diabetes defined as patients with a Hemoglobin A1C (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.

You may not qualify if:

• 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 (alanine aminotransferase (ALT), aspartate aminotransferase (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 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG Co-A) inhibitors , fibrates, niacin, ezetimibe, 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 inhibit 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

Sponsors & Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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. doi: 10.1016/j.ecl.2005.01.010.

  PMID: 15850845 BACKGROUND

• 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.

  PMID: 19470627 BACKGROUND

• 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. doi: 10.1196/annals.1367.009.

  PMID: 17148736 BACKGROUND

• Gubbi S, Muniyappa R, Sharma ST, Grewal S, McGlotten R, Nieman LK. Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals. J Clin Endocrinol Metab. 2021 Apr 23;106(5):1501-1515. doi: 10.1210/clinem/dgab046.

  PMID: 33507248 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Endocrine System Diseases; Diabetes Mellitus; Cushing Syndrome; Glucose Intolerance

Interventions

Mifepristone

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Hyperglycemia

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Lynnette Nieman MD
• Organization: NIDDK, NIH

NiemanL@nih.gov

301-496-8935

Study Officials

• Lynnette K Nieman, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2011
• First Posted: August 18, 2011
• Study Start: November 29, 2011
• Primary Completion: November 24, 2015
• Study Completion: November 24, 2015
• Last Updated: April 14, 2021
• Results First Posted: April 14, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: Upon publication, for two years
• Access Criteria: plan for data use

Locations

US (1)