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Mifepristone Effects on Glucose Intolerance in Obese/Overweight Adults

Primary Purpose

Endocrine Disease, Diabetes

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Mifepristone
Placebo
Sponsored by
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Endocrine Disease focused on measuring Metabolism, Cortisol, Hypercortisolism, Glucose Intolerance

Eligibility Criteria

35 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

  • INCLUSION CRITERIA:

    1. Men and women 35 - 70 years of age
    2. Subjects will be overweight or obese, with body mass index (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 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.

    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 (alanine aminotransferase (ALT), aspartate aminotransferase (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 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
  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 inhibit 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 (thyroid stimulating hormone and Free thyroxine (FT4) 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 corrected Q-T interval (QTc) on electrocardiogram
  24. Unable to give informed consent

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Mifepristone, then Placebo

Placebo, then Mifepristone

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change in Insulin Sensitivity Index
insulin sensitivity index based on the effect of insulin on glucose during frequently sampled intravenous glucose tolerance test (FSIVGTT)

Secondary Outcome Measures

Change in Fasting Plasma Glucose
fasting plasma glucose after study agent compared to baseline
Change in Fasting Insulin Levels
Fasting insulin after study agent administration compared to baseline
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
HOMA-IR is an index of insulin resistance, measured as glucose in mmol/L x insulin in mIU/mL)/22.5. HOMA-IR > 2.5 indicates insulin resistance.
Adipose-tissue Insulin Resistance Index (Adipo-IR)
The adipose tissue insulin resistance index (Adipo-IR), a surrogate measure for fasting adipose-tissue insulin resistance, was calculated as the product of fasting insulin and fasting free fatty acids (FFA)
Adipose-tissue Insulin Sensitivity Index (Adipo-SI)
The Adipo-SI was calculated as ratio of the slope of the linear decrease in natural log transformed FFA [Ln (FFA) slope] during the first 90 minutes of the FSIVGTT and the area under the curve (AUC) of insulin during that 90-minute period (AUC Insulin 0-90 min).

Full Information

First Posted
August 17, 2011
Last Updated
March 19, 2021
Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT01419535
Brief Title
Mifepristone Effects on Glucose Intolerance in Obese/Overweight Adults
Official Title
Effects of the Glucocorticoid Antagonist, Mifepristone, on Glucose Intolerance in Obese and Overweight Individuals
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
November 29, 2011 (Actual)
Primary Completion Date
November 24, 2015 (Actual)
Study Completion Date
November 24, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endocrine Disease, Diabetes
Keywords
Metabolism, Cortisol, Hypercortisolism, Glucose Intolerance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Mifepristone, then Placebo
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo, then Mifepristone
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Mifepristone
Other Intervention Name(s)
55245, 11β-[p-(Dimethylamino)phenyl]-17α-(1-propynyl)estra-4,9-dien-17β-ol-3-one
Intervention Description
Mifepristone 50mg tablet by mouth every six hours for nine days.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
inert look-alike tablet
Intervention Description
Placebo (matching mifepristone 50mg tablet) by mouth every six hours for nine days.
Primary Outcome Measure Information:
Title
Change in Insulin Sensitivity Index
Description
insulin sensitivity index based on the effect of insulin on glucose during frequently sampled intravenous glucose tolerance test (FSIVGTT)
Time Frame
Nine days
Secondary Outcome Measure Information:
Title
Change in Fasting Plasma Glucose
Description
fasting plasma glucose after study agent compared to baseline
Time Frame
Nine days
Title
Change in Fasting Insulin Levels
Description
Fasting insulin after study agent administration compared to baseline
Time Frame
9 days
Title
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Description
HOMA-IR is an index of insulin resistance, measured as glucose in mmol/L x insulin in mIU/mL)/22.5. HOMA-IR > 2.5 indicates insulin resistance.
Time Frame
9 days
Title
Adipose-tissue Insulin Resistance Index (Adipo-IR)
Description
The adipose tissue insulin resistance index (Adipo-IR), a surrogate measure for fasting adipose-tissue insulin resistance, was calculated as the product of fasting insulin and fasting free fatty acids (FFA)
Time Frame
9 days
Title
Adipose-tissue Insulin Sensitivity Index (Adipo-SI)
Description
The Adipo-SI was calculated as ratio of the slope of the linear decrease in natural log transformed FFA [Ln (FFA) slope] during the first 90 minutes of the FSIVGTT and the area under the curve (AUC) of insulin during that 90-minute period (AUC Insulin 0-90 min).
Time Frame
9 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
INCLUSION CRITERIA: 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). OR 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. 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 (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 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 (thyroid stimulating hormone and Free thyroxine (FT4) 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 corrected Q-T interval (QTc) on electrocardiogram Unable to give informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lynnette K Nieman, M.D.
Organizational Affiliation
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Upon reasonable request, individual participant data will be shared with other investigators
IPD Sharing Time Frame
Upon publication, for two years
IPD Sharing Access Criteria
plan for data use
Citations:
PubMed Identifier
15850845
Citation
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.
Results Reference
background
PubMed Identifier
19470627
Citation
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.
Results Reference
background
PubMed Identifier
17148736
Citation
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.
Results Reference
background
PubMed Identifier
33507248
Citation
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.
Results Reference
derived
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2011-CH-0208.html
Description
NIH Clinical Center Detailed Web Page

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Mifepristone Effects on Glucose Intolerance in Obese/Overweight Adults

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