Clinical trial NCT01419535
Conditions: Endocrine Disease Diabetes
Keywords: Metabolism Cortisol Hypercortisolism Glucose Intolerance
Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Start date: 2011-11-29; Completion date: 2015-11-24
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: 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 2: 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.
Interventions: intervention 1: Mifepristone intervention 2: Placebo
Intervention descriptions: intervention 1: Mifepristone 50mg tablet by mouth every six hours for nine days. intervention 2: Placebo (matching mifepristone 50mg tablet) by mouth every six hours for nine days.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
        IRB submission CR 11-16-17 
1 
Project Number:  11-CH-0208 
 
Drug/Device:  
Mifepristone  IND 113698 
9,11,12,12-[2H]4-cortisol  IND 113698  
 
 
Subject:  Effects of the glucocorticoid antagonist, mifepristone, on glucose intolerance in obese 
and overweight individuals 
 
Identifying words: Glucose intolerance, cortisol, Mifepristone, glucocorticoid antagonist 
 
Principal Investigator and Accountable Investigator 
Lynnette K. Nieman, M.D., Senior Investigator, DEOB, NIDDK Bldg 10, CRC 1E-3140* 
Intramural Associate Investigators 
Ninet Sinaii, Ph.D., Biostatistics and Clinical Epidemiology Service, CC, 10/2N228 
Raven McGlotten, MSN, RN, DEOB, NIDDK 10/1-3140* 
Susmeeta T. Sharma, M.B.B.S., NIH Special volunteer 
 
*investigators who may obtain informed consent 
 
Extramural Associate Investigator 
Brian R. Walker M.D., Endocrinology Unit, Queen's Medical Research Institute, Centre for 
Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, 
Scotland, UK 
Proposed Start Date:  June 1, 2011 
Estimated Duration of Accrual:  Five years 
Subjects of Study:    Men and women (35 - 70 yrs) with glucose intolerance 
Number:  80  
Project uses ionizing radiation?  No 
Off-Site project?  No 
Multi-Institutional Project?  No 
 
Precis 
 
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 


 
 
        IRB submission CR 11-16-17 
2 
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. 


 
 
        IRB submission CR 11-16-17 
3 
 
Table of Contents 
 
 
 
Section 
Page 
Background 
4 
Study Hypothesis 
6 
Study Design and Methods 
7 
Study Analysis 
13 
Pharmaceutical Safety and Randomization 
13 
Evaluation of Benefits and Risks/Discomforts 
14 
Human Subjects Protection 
17 
Confidentiality and Use of Retained Specimens  
17 
Remuneration of Subjects 
17 
References 
18 


 
 
        IRB submission CR 11-16-17 
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BACKGROUND 
 
Cortisol is an important regulator of metabolism that modulates the use of glucose and fat 
as fuels. Elevated cortisol levels in Cushing’s syndrome lead to obesity, hypertension, dyslipidemia 
with elevated triglyceride (TG) levels and low high-density lipoprotein (HDL) levels, and type 2 
diabetes mellitus (1). These disorders also are common in the general population, in the absence 
of Cushing’s syndrome.  In people without Cushing’s syndrome, the constellation of abnormalities 
is often referred to as the “Metabolic Syndrome” based on the extent of the abnormalities. Some 
individuals with Metabolic Syndrome seem to have mild functional hypercortisolism, which may 
contribute to the pathogenesis of the syndrome (2 - 5).  Also, some individuals with abdominal 
obesity have increased urinary free cortisol (UFC) levels, loss of diurnal cortisol rhythm, and 
abnormal HPA axis suppression after dexamethasone (5 - 6), similar to the biochemical 
abnormalities seen in Cushing’s syndrome. Excess glucocorticoids in Cushing’s syndrome are 
known to favor visceral fat deposition (7).  However, many individuals with obesity do not have 
abnormal cortisol tests (8).  Taken together, these data have led to the hypothesis that cortisol 
may be involved in development of abdominal obesity, glucose intolerance and other components 
of the Metabolic Syndrome, either because of subtle increases in circulating levels, or because of 
increased tissue exposure due to local metabolism.  
  
 
 
  
Associations between tissue levels of cortisol, obesity and glucose tolerance 
 
Circulating cortisol levels are mostly normal in people with central obesity, insulin resistance 
Metabolic Syndrome (2 - 3), leading to speculation that increased local tissue exposure to cortisol 
or its active metabolites may be critical in development of these disorders.  One possibility is that 
there is increased local regeneration of cortisol from corticosterone.  The 11β-hydroxysteroid 
dehydrogenase (11BHSD) enzymes interconvert hormonally inactive glucocorticoids such as 
cortisone and dehydrocorticosterone and their active forms, cortisol and corticosterone. The renal 
11BHSD2 enzyme catalyzes the conversion of cortisol to (inactive) cortisone, thus reducing 
mineralocorticoid effects of cortisol.  The 11BHSD1 enzyme is more widely expressed (in liver, 
adipose, bone, and the central nervous system) and functions primarily as a reductase (converting 
cortisone to cortisol) (9 - 10). This 11BHSD1 reductase activity requires subcellular NADPH cofactor 
generation by hexose-6-phosphate dehydrogenase, and in its absence, this bi-directional enzyme 
can convert cortisol to cortisone.   Intracellular cortisol levels may thus be modulated by 
conversion of cortisone to cortisol by 11BHSD1, and this may contribute to the development of 
glucose intolerance and the Metabolic Syndrome (11).  
 
Because urinary levels of cortisol, cortisone, and their metabolites reflect integrated (total) 
body metabolism (including the kidney), they cannot be used to assess the contribution of specific 
tissue components.  As a result, 11BHSD effects have been assessed using enzymatic assays of 
activity, measurement of mRNA expression in specific tissues, or measurement of conversion of 
cortisol or cortisone labeled with stable isotopes. 
11BHSD1 expression and activity has been found to be elevated in both visceral and 
subcutaneous fat depots in obese individuals (12 - 13). Purnell and colleagues studied eight obese 
men before and after weight loss and looked at daily cortisol production and clearance rates, 
intraabdominal fat (IAF) and subcutaneous fat (SQF) by computerized tomography, insulin 


 
 
        IRB submission CR 11-16-17 
5 
sensitivity (SI) by frequently sampled intravenous glucose tolerance tests, and subcutaneous 
adipocyte 11BHSD1 gene expression by quantitative RT-PCR.  They found that increased cortisol 
production rates and free cortisol levels correlated with increased IAF and decreased insulin 
sensitivity but not with subcutaneous fat. Increased 11BHSD1 expression correlated with both IAF 
and SQF and with decreased SI.  With greater loss in body fat than lean mass with weight loss, 
11BHSD1 expression was found to be decreased from baseline (13). These data support a role for 
increased local (tissue) cortisol exposure leading to visceral fat deposition and insulin resistance.  
Many investigators have suggested that increased cortisol release from the omentum into 
the portal vein contributes to hepatic insulin resistance associated with central obesity.  However 
in vivo studies of obese non-diabetic individuals using stable isotopes suggest that splanchnic 
cortisol is derived entirely from the liver and that there is no cortisol release from the visceral 
tissue into the portal vein (–14 - 15). On the contrary, visceral tissue releases cortisone into the 
portal venous system, thus potentially providing increased substrate for hepatic conversion to 
cortisol (9). This cortisone release from the visceral tissue occurs in the presence of low levels of 
11BHSD2 mRNA in visceral fat. Therefore the exact mechanism by which cortisone is generated is 
not clear. It is possible that in some situations 11BHSD1 has a predominately dehydrogenase 
(inactivating) activity leading to cortisone production (16 - 17).  
It should be mentioned that some studies do not show a depot difference in 11BHSD1 
mRNA expression and have suggested that under steady state conditions, increased local 
production of cortisol is unlikely to contribute to omental adipose tissue function (18). These 
discrepancies in study results are likely related to differences in assays for measuring 11BHSD 
activity, the use of different cells or explants and the effects of renal 11BHSD2. Also, in vitro 
studies may not faithfully reproduce the in vivo environment, and therefore may result in a false 
preponderance of reductase or dehydrogenase activity.   
 
Although glucocorticoids have been shown to induce 11BSHD1 expression in vitro, a single 
study looking at omental levels of 11BHSD1 in Cushing’s syndrome patients found its expression to 
be similar to those of lean individuals (19).  However, as omental fat mass is generally increased in 
patients with Cushing’s syndrome, the net hormonal conversion cannot be ascertained.  
Moreover, it is possible that high cortisol levels overwhelm the 11BHSD1 enzyme, as seen with 
11BHSD2 enzyme in the kidneys (20), so that excess cortisol is delivered to the liver.  
 
Genetically engineered mouse models provide additional evidence for a potential pathologic 
role for 11BHSD.  Mice that over-express 11BHSD1 in the liver develop fatty liver, hypertension, 
and mild insulin resistance without altered fat depot mass (21). On the other hand, transgenic 
mice overexpressing 11BHSD1 selectively in adipose tissue exhibit a full metabolic syndrome with 
visceral obesity, hyperlipidemia, insulin resistance/diabetes and hypertension (22). 
 
Other types of local cortisol metabolism may contribute to excess tissue glucocorticoid 
exposure.  Reduction of glucocorticoids to A-ring reduced dihydro- and tetrahydro-derivatives by 
means of hepatic 5 α- and 5 β-reductases was previously regarded as the final inactivation 
pathway. However, studies in rats have shown that corticosterone, 5 α- tetrahydrocorticosterone 
(5αTHB), and 5 α –dihydrocorticosterone (5αDHB) are similarly effective in displacing tritiated 
dexamethasone from binding sites in hepatocytes while the 5β metabolites have less effective 
binding. In addition, 5αTHB, but not the 5β-reduced metabolites, activated the glucocorticoid 
receptor in vitro and suppressed ACTH in vivo, and these effects were inhibited by mifepristone 
(23).  Increased 5α reduced metabolites have also been seen in patients with diabetes and women 
with polycystic ovary syndrome (PCOS). These findings suggest that this pathway may be involved 


 
 
        IRB submission CR 11-16-17 
6 
in the development of glucose intolerance and Metabolic Syndrome (24 - 25).  
 
 
The link of cortisol to insulin resistance and the Metabolic Syndrome is further substantiated 
by studies looking at the effects of mifepristone. Liu and colleagues investigated the role of tissue 
glucocorticoids in type 2 diabetes mellitus and obesity by analyzing the expression of 
glucocorticoid receptor and 11BHSD1 in the hepatocytes of db/db mice (a model of type 2 
diabetes mellitus). Increased expression of glucocorticoid receptor and 11BHSD1 was associated 
with elevated levels of corticosterone, insulin, and blood glucose. They also found that 
intraperitoneal administration of mifepristone to the db/db mice for 3 weeks improved glucose 
tolerance with simultaneous decrease in the expression of 11BHSD1 and glucocorticoid receptor in 
the liver (26).  These findings were corroborated in another study on ob/ob diabetic mice (27).  
Also, administration of mifepristone to obese Zucker rats and db/db mice prevents high fat diet-
induced weight gain and type-2 diabetes (28 - 29).   
 
In humans, mifepristone successfully ameliorated hypercortisolemia-related effects in 
patients with Cushing’s syndrome (30).  More recently mifepristone was approved by the FDA for 
treatment of chronic hyperglycemia of uncontrolled Cushing’s syndrome (31). In healthy men, 
administration of 400 mg of mifepristone at 2200h led to a decrease in triglyceride levels, despite 
compensatory increases in cortisol (32).  Bertagna et al. looked at the antiglucocorticoid effect of 
mifepristone in four healthy men and found that ACTH and cortisol values increased 6 - 10 hours 
after administration of 400 mg of mifepristone at 0200 h, but not at 1400 h. Although this was a 
small study, it demonstrates the fact that the antiglucocorticoid effect of mifepristone on the 
hypothalamic-pituitary unit may occur only at certain times of the day (33), and supports the use 
of a split dosing regimen rather than a single daily dose, to minimize effects on ACTH.   
 
Based on the putative role of excessive exposure to cortisol, we hypothesized that reduction 
in cortisol action with mifepristone might reverse glucose intolerance and some of the other 
components of the metabolic syndrome, just as it reverses the features of Cushing’s syndrome 
(30).  
 
The long-term aim of this study is to evaluate the ability of mifepristone to reverse or 
improve the components of Metabolic Syndrome, specifically impaired fasting glucose, 
dyslipidemia, hypertension and visceral obesity. This pilot study will specifically investigate the 
effects of short-term administration of mifepristone on insulin sensitivity. A second phase of the 
study will then look at the effects of long-term treatment on lipids, blood pressure, weight as well 
as glucose intolerance.   
 
 
 
STUDY HYPOTHESIS 
The primary study hypothesis is that glucose abnormalities in overweight and obese 
individuals will improve with short-term administration of the glucocorticoid antagonist 
mifepristone. 
A secondary study hypothesis is that activation of the HPA axis will be minimal when 
mifepristone is administered in four divided daily doses of 50 mg.     
 
STUDY DESIGN AND METHODS 
 
Prospective, randomized, placebo-controlled, cross-over study 


 
 
        IRB submission CR 11-16-17 
7 
 
Inclusion Criteria: 
 
1. Men and women 35 – 70 years of age 
2. Overweight or obese subjects with BMI ranging from 25 - 37 kg/m2.  
3. Subjects will have pre-diabetes defined as fasting glucose ≥ 100 mg/dL or a 2-hour glucose 
value ≥ 140 mg/dl during an oral glucose tolerance test (OGTT)  
OR 
Mild diabetes defined as patients with a Hba1c ≤ 7% on no medications (diet-controlled) or 
on a stable dose of metformin and no other hypoglycemic agents for ≥ 3 months before 
study entry.  
4. Willing and able to comply with study requirements. 
 
Exclusion Criteria: 
1. Pregnancy and lactation 
2. Change in dose of metformin or use of hypoglycemic agents other than metformin for 
treatment of diabetes within 3 months of study entry. Diagnosis of diabetes will be based 
on the 2011 American Diabetes Association guidelines: Hba1c ≥ 6.5%, fasting plasma 
glucose ≥ 126 mg/dl, 2-hour glucose ≥ 200 mg/dl during an OGTT, or a random blood 
glucose ≥ 200 mg/dl along with classic symptoms of hyperglycemia (34) 
3. Uncontrolled hypertension (blood pressure ≥ 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 for 
women and > 3 alcoholic drinks per day for men. Subjects will be screened for depression 


 
 
        IRB submission CR 11-16-17 
8 
using the well-validated physician health questionnaire-9 (PHQ-9) with a score cut-off of ≥ 
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 
 
Study protocol 
 
Screening 
Subjects will undergo evaluation at the Clinical Center for eligibility.  This will include 
measurement of height, weight, waist circumference, blood pressure, and a detailed history and 
physical examination. Subjects will be screened for depression using the PHQ-9 questionnaire. If a 
subject is found to have severe depression or suicidal ideation, they will be seen by a psychiatrist 
at NIH on an emergent basis and further management will be guided by their recommendations. 
An electrocardiogram will be obtained to identify any subjects with QTc interval prolongation. 
Screening laboratory tests will include a serum pregnancy test for females, fasting plasma glucose, 
HgbA1c, OGTT (2 hour, after 75 g dextrose), comprehensive metabolic panel, CBC with differential, 
coagulation profile, midnight salivary cortisol, TSH, Free T4, FSH and LH levels.   HIV 1&2 antibody 
and hepatitis C antibody levels will also be checked if on history taking the subject is found to have 
risk factors for HIV or Hepatitis C. A transvaginal ultrasound will be obtained to evaluate 
endometrial thickness in postmenopausal women (defined as amenorrhea for ≥ 12 months and an 
FSH level in the postmenopausal range) as well as those in the perimenopausal phase 
(amenorrhea for ≥ 6 months and FSH level in the postmenopausal range). An MRI Pelvis will be 
performed only if the transvaginal ultrasound is unable to provide an accurate measurement of 
the endometrial stripe. Subjects in whom a definite assessment of endometrial thickness cannot 
be obtained with either ultrasound or MRI (as may be the case in patients with multiple fibroids) 
will be followed closely for any signs of abnormal vaginal bleeding and will undergo a repeat 
transvaginal ultrasound upon completion of the study.  
 
Study for eligible subjects 
 
 
 
This crossover study has two treatment arms (placebo or Mifepristone 50 mg tablets every 
six hours) with each subject serving as her own control. After eligibility is confirmed, subjects will 
undergo baseline testing and will be randomized to one of the treatment arms.  Testing will be 
performed before and at the end of seven days of treatment with the study agent. Study drug will 
be continued until completion of post-drug testing.  Thus, subjects will take the study drug for a 
total of nine days during each treatment arm. There will be a washout period of at least six and no 
more than eight weeks after which subjects will be randomized to the other arm of the study with 
an identical testing schedule. Subjects will record any symptoms or adverse events on a calendar 


 
 
        IRB submission CR 11-16-17 
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throughout the study. Women will be asked to keep a record of any abnormal menstrual bleeding. 
Subjects will be asked not to start on any new diet or exercise regimen during the study and 
maintain a stable weight for at least 2 weeks prior to study entry. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures during each treatment 
 
Subjects will be admitted to the 5SWN metabolic unit or 5NW in the Clinical Center on a 
Sunday for testing the following day. To accommodate menstrual cycle timing, and for subjects for 
whom weekend testing is preferable, admission may occur on Friday or Saturday; additionally the 
Day 2 and 3 testing may be swapped if needed to accommodate nursing scheduling.  To reduce 
potential variability associated with estrogen in premenopausal women, testing will be performed 
in the early follicular phase (days 1-7 of menstrual cycle). In case of perimenopausal women with 
irregular menstrual cycles, an attempt will be made to begin testing in the early follicular phase 
with the rest of the testing performed at pre-determined study intervals. Height, weight, and 
waist, hip and neck circumference (mean of three measurements) will be measured. Waist 
circumference will be measured at the intersection of midaxillary line with the uppermost lateral 
border of the right iliac crest at the end of a normal expiration (36). The hip circumference will be 
measured in a horizontal plane at the level of the maximal circumference of hips and buttocks. 
Neck circumference will be measured at mid-neck height between the mid-cervical spine and mid 
anterior neck to within 1 mm (37). Weight will be measured at the same time of the day on the 
same scale. All measurements will be taken after an overnight fast with the subject standing 
upright, both arms hanging loosely by the side of body, and eyes directed straight ahead. Subjects 
will be maintained on an isocaloric regular diet during the inpatient part of the study. Those 
subjects who are on metformin at the time of study entry will be maintained on the same dose of 
metformin throughout the study. 
 
Day 1 (Monday) 
•  Fasting blood pressure will be measured consecutively three times five minutes apart.  Blood 
pressure will be measured in a standardized manner in the morning using equipment that meets 
certification criteria. Measurements will begin after at least 5 minutes of rest in a supine position. 
Subjects will be asked to refrain from smoking or ingesting caffeine during the 30 minutes 
preceding the blood pressure measurement.  Blood pressure will be measured in the same arm on 
Screening 
visit 
Treatment Period 1 
Treatment Period 2 
Safety visit- Day 19 & 33 
6 – 8 week washout 
Randomized to Mifepristone 
Randomized to Placebo 
Randomized to Mifepristone 
Randomized to Placebo 
Day 1                        Day 12 
Day 1                     Day 12  
Safety visit - 
Day 19 & 33 
Figure 1: Study Design overview 


 
 
        IRB submission CR 11-16-17 
10 
each occasion using an appropriate cuff size with the bladder in the cuff encircling at least 80 
percent of the arm for accurate measurement.  
•  Morning fasting baseline laboratory measurements:  serum levels of lipids (total cholesterol, 
HDL and low density lipoprotein (LDL) cholesterol, triglycerides, VLDL), glucose, total and free 
testosterone, androstenedione, DHEAS, comprehensive metabolic panel, ACTH and cortisol.   
• ACTH and cortisol levels will be measured hourly for 24 hours from 0900h to 0900h the next day; 
urine will be obtained during this time for measurement of 5 alpha and beta-reduced cortisol 
metabolites, cortisol, cortisone and their tetra-hydro metabolites in collaboration with Dr. B. 
Walker.  
• Glucose levels will be measured before and two hours after breakfast, lunch, and dinner.   
 
Day 2 (Tuesday):  
 
Subjects will undergo an insulin-modified frequently sampled intravenous glucose tolerance test 
(FSIVGTT) when the urine collection is finished.  Two indwelling intravenous catheters will be 
placed – one for sampling and other for infusing glucose and insulin. A bolus of 50% dextrose (0.3 
gm/kg) will be administered over ~ 1 minute. Blood samples will be obtained for measurement of 
glucose, insulin, and free fatty acids (FFA) at -10, -1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, and 19 
minutes. At 20 minutes, an insulin bolus (0.03 units/kg) will be administered and samples for 
insulin, glucose, and FFA will be collected at 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 
150, and 180 minute time points.  The data will be analyzed by Bergman method to calculate the 
insulin sensitivity index (Si) (38 - 39). Subjects will be allowed to go on pass if they can return by 8 
AM. 
A fasting lipid panel will also be obtained along with baseline labs. 
 
Day 3 (Wednesday):  
A 75 gram 3 hour OGTT with measurement of insulin, c-peptide and glucose levels at -5, 0, +30, 
+60, +90 +120, +150 and +180 min will be performed on day 3 before and after the study drug.   
 
Serial blood draws for Day 1 (serial ACTH/cortisol measurements) and Day 3 (OGTT) will be 
obtained within 5 minutes of the appointed time. After the conclusion of Day 1 through Day 3 
testing, subjects will be sent on pass with the study drug with instructions to begin at 6 PM, and to 
continue at 6-hour intervals.   
 
Day 4 – 9:  
Study participants will take the study drug as instructed for seven days and will return on day 10 of 
the study, bringing the remaining study medication with them. Study drug will be continued until 
all study procedures are complete on day 12 (study drug given for a total of 9 days). 
 
Day 9 (Tuesday): Subjects will be readmitted to 5SWN or 5NW 
 
Day 10 – 12 (Wednesday-Friday):  
After an overnight fast, all study procedures indicated for day 1 -3 will be repeated on day 10 - 12. 
Blood (5 ml) will be obtained on day 10 for measurement of post-treatment mifepristone level and 
to hold for other potential measurements related to cortisol metabolism. Subjects will continue on 
the study drug until the completion of all study procedures on day 12.  


 
 
        IRB submission CR 11-16-17 
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Day 19 and 33 (Friday):  Safety monitoring 
After discontinuation of study drug, subjects will return approximately one week (Day 19) and 
then 3 weeks (Day 33) after the last day of study drug intake for measurement of blood 
chemistries and CBC.  The research team will make every effort to ensure that these safety follow-
up visits are within 2 days of day 19 and day 33. However, for subject convenience, we will allow 
for the follow-up visits to be within 5 days of the expected date of follow-up (day 19 ± 5 days and 
day 33 ± 5 days). In these cases, a member of the study team will contact the study subject on the 
expected date of follow-up to ensure that the subject is doing well.  If any potential treatment-
related abnormalities/adverse events are noted at the safety visits, subjects will receive 
appropriate treatment for these abnormalities and will be followed closely as clinically indicated 
until the abnormalities/adverse events have fully resolved.  
 
Second study treatment visit:  These study procedures will be repeated with each study drug after 
a wash-out period of 6-8 weeks.  
 
For subject convenience, we will allow for the pre-study drug testing (Days 1 through 3) in each 
treatment arm to be done on days other than as specified above as long as it is done no more than 
10 days prior to study drug initiation.  
 
Table 1: Schema for first admission testing.  The second admission will be identical.  
Sunday  Monday  
Tuesday  
Wednesday  
Thursday  
Friday  
Saturday  
 
Admit 
to 
5SWN 
or 5NW 
DAY 1  
Fasting labs  
24 hr urine  
 
0900  
Serial 24 h 
ACTH/Cortisol  
 
Pre & post 
prandial 
glucose levels  
DAY 2  
0900 
Complete 
serial 
ACTH/Cortisol  
 
0930  
Fasting lipids 
FSIVGTT 
 
Can go out on 
pass  
DAY 3 
0800  
3 hr OGTT 
 
1800  
START 
MIFEPRISTONE  
OR PLACEBO 
 DAY 4 
On pass  
DAY 5 
On pass  
DAY 6 
On pass  
DAY 
7On 
pass  
DAY 8 
On pass  
DAY 9 
Return from 
pass to 5SWN  
DAY 10  
Fasting labs  
24 hr urine 
 
0900  
Serial 24h 
ACTH/Cortisol 
  
Pre & post 
prandial 
DAY 11  
0900  
Complete 
serial 
ACTH/Cortisol   
  
0930  
Fasting lipids 
FSIVGTT 
 
Day 12 
3h OGTT 
STOP 
MIFEPRISTONE 
OR PLACEBO 
 
Discharge  
 


 
 
        IRB submission CR 11-16-17 
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glucose levels  
 
 
 
 
  
DAY 19 and 33 
Follow-up 
 
 
 
 
Measurement of 11BHSD activity 
Subjects will also undergo measurement of 11BHSD activity at least after one and no more than 
two months after the last day of study drug intake in the second treatment arm. This will be 
performed using 20% 9,11,12,12-[2H]4-cortisol and 80% hydrocortisone, as reported by Andrew et 
al (kindly provided by Dr. Brian Walker) (40). At time zero ( 0830 h), a primed intravenous infusion 
of cortisol (20% 9,11,12,12-[2H]4-cortisol and cortisol) is given (3.6 mg priming bolus, then 
continuous 1.74 mg/h infusion) for three hours and 20 minutes. Blood is obtained at times -5, 0, 
60, 120, 180, 185, 190, 195 and 200 minutes. This test will only be performed once during the 
study. This part of the study is currently on clinical hold. 
 
Study Outcomes 
 
Primary Outcome 
1.  Change in insulin sensitivity index based on the effect of insulin on glucose metabolism in the 
FSIVGTT. 
 
Secondary Outcomes 
1. 
Change in fasting plasma glucose and insulin levels. 
2. 
Change in area under the curve (AUC) insulin, AUCglucose/AUCinsulin, and insulin sensitivity 
index based on OGTT. 
3. 
Change in pre- and post-prandial glucose levels.  
4. 
Change in basal triglyceride level.   
5. 
Change in free fatty clearance based on the effect of insulin on FFA in the FSIVGTT. 
6. 
Change in HDL, LDL, and total cholesterol levels. 
4. 
Change in weight, BMI, neck, waist and hip circumference.  It is unlikely that these parameters 
will change with the short duration of administration, however. 
5. 
Change in blood pressure. It is unlikely that these parameters will change with the short 
duration of administration, however. 
6. 
 Whole-body rate of regenerating cortisol (measured with 9,11,12,12-[(2)H(4)]cortisol tracer) 
will be analyzed in collaboration with Dr. Brian Walker. On metabolism by dehydrogenation, d4F 
loses 11alpha- deuterium, forming trideuterated cortisone (d3E) and is regenerated by reduction 
to tri-deuterated cortisol (d3F). 11BHSD1 reductase activity can be measured specifically as 
conversion of d3E to d3F (40). The amount of regenerated cortisol at baseline will be assessed for 
correlation with basal measures of insulin sensitivity and triglyceride levels, and the change in 
these parameters in response to mifepristone.    
7.  Adverse events will be tallied and compared between treatments. 


 
 
        IRB submission CR 11-16-17 
13 
8.  Change in total and free testosterone, androstenedione, DHEAS, ACTH and cortisol will be 
assessed between treatments as a measure of mifepristone effect. 
9. Change in 5 alpha and beta-reduced cortisol metabolites, cortisol, cortisone and their tetra-
hydro metabolites will be assessed between treatments. 
10.  Correlation between post-treatment mifepristone level and the change in triglyceride levels 
and insulin sensitivity in response to mifepristone.   
 
 
STUDY ANALYSIS 
 
The study will be analyzed in collaboration with Dr. Ninet Sinaii, Ph.D. (Biostatistics and 
Clinical Epidemiology Service, Clinical Center).  Subjects will be randomized in blocks of 6 into the 
two treatment arms.  Means and standard deviations will be used to describe continuous data. 
Proportions and frequencies will be used to describe categorical data.  All continuous data will be 
examined for normality and homogeneity of variances, and will be either transformed as 
appropriate or assessed using non-parametric tests. The change in continuous variables (including 
triglyceride, HDL, LDL and total cholesterol levels, insulin sensitivity index, pre- and post-prandial 
glucose values, whole body cortisol production rates, blood pressure, weight, and waist 
circumference) before and after study intervention will be analyzed using paired t-tests or 
Wilcoxon signed-rank test.  Correlation of continuous data (e.g., regenerated cortisol and insulin 
sensitivity and triglyceride levels, and mifepristone level and insulin sensitivity and triglyceride 
response) will be carried out by Pearson’s correlation coefficient or Spearman’s rho, as 
appropriate.  Between and within treatment comparisons will be done using Mixed Models for a 
crossover design that will also consider sequence effect, if any. Difference in the proportion of 
subjects who meet criteria for metabolic syndrome, or other categorical data, before and after 
study intervention will be analyzed using McNemar’s test. Two-sided p-values will be used for all 
analysis and the level of statistical significance will be set a priori at 0.05. The stepdown Bonferroni 
correction will be used to adjust for multiple comparisons. All statistical analysis will be performed 
using SAS v. 9.2 (SAS Institute, Cary, NC). 
Human data on the effect of mifepristone on insulin sensitivity index are lacking. This will 
therefore be a pilot study of 17 subjects. Data from this study will then be used to design a long-
term study looking at the effect of mifepristone on glucose intolerance, lipids, weight and blood 
pressure. With an estimated loss-to-follow-up rate of 15%, we would need to recruit a total of 25 
patients. Thus, we plan to screen approximately 80 patients to account for the high ineligibility 
rate and patient drop-outs prior to study initiation.  
Based on current evidence, a compensatory rise in ACTH levels has been seen with 
mifepristone in healthy individuals at doses as low as 100 mg/day (when used as a single dose over 
3 months) and 200 mg/day over 8 days (41 - 42). Given the uncertainty in the effect of the dose, 
we plan to do an interim analysis looking at the effect of the proposed dose (50 mg every 6 hours) 
on the HPA axis in the first 6 subjects (one randomization block). The data from the first 6 subjects 
will be unblinded to Dr. Ninet Sinaii, the study statistician, only.  If the 24 hour UFC value post 
mifepristone treatment is more than or equal to twice the upper limit of normal in four or more of 
the six subjects, then we will decrease the mifepristone dose to 25 mg every 6 hours (100 
mg/day). However, if there is no significant increase in the levels (< twice the upper limit of 
normal), same dose of mifepristone will be continued throughout the study. If the mifepristone 


 
 
        IRB submission CR 11-16-17 
14 
dose is changed based on the results of the interim analysis, then the data from the first six 
subjects will not be used in the final analysis and 15 additional subjects will be enrolled prior to 
completion of the study. On the other hand, if no dose adjustment is required, the study analysis 
will be done as previously planned.  
 
PHARMACEUTICAL SAFETY AND RANDOMIZATION 
 
 
Mifepristone (HRA 052015; INN Mifepristone) is a cortisol and progesterone analog with 
antiprogestin and antiglucocorticoid activity. Healthy subjects receiving long-term mifepristone 
administration showed antiglucocorticoid effects at a daily dose of 10 mg/kg, which is about 5 – 10 
fold greater than that required to demonstrate antiprogestin effects (43).  The agent effectively 
reverses the clinical and glucocorticoid-dependent biochemical features of Cushing’s syndrome 
(30).  The proposed doses in this protocol are about 2 – 3 mg/kg/d. 
 
Mifepristone will be given under an active IND (113,698) sponsored by Laboratoire HRA-
Pharma. Laboratoire HRA-Pharma, NICHD’s cooperative research and development partner, will 
provide mifepristone compound. The Pharmaceutical Development Service will formulate the 
compound into 50 mg capsules.   Mifepristone will be manufactured, controlled and released 
according to current GMP guidelines. A look-alike inert placebo will be formulated into capsules by 
the Pharmaceutical Development Service.  
 
The Pharmaceutical Development Service will randomize subjects in blocks of 6 to receive 
the two treatments.  The investigators will not be informed of the treatment group of any 
participant while she receives study compound unless there is an adverse event requiring 
“unblinding” of the treatment.  At the interim analysis, the treatment arm assignment for the first 
6 subjects will only be revealed to Dr. Ninet Sinaii, the study statistician. The rest of the study 
investigators will remain blinded.  
The 20% 9,11,12,12-[2H]4-cortisol and 80% hydrocortisone solution will be given under an 
active IND (113,698) sponsored by HRA-Pharma. The deuterated cortisol will be purchased from 
Cambridge Isotope Laboratories, Inc (50 Frontage Rd, Andover, MA.  01810-5413; phone 800-322-
1174; WEB: www.isotope.com). The Pharmaceutical Development Service will perform sterility 
and pyrogenicity testing and will formulate the 20% 9,11,12,12-[2H]4-cortisol and 80% 
hydrocortisone solution. 
 
 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
 
 
Benefits 
Subjects may benefit by receiving a physical examination, and laboratory testing. In addition this 
study will contribute to our understanding of the physiology pertaining to the HPA axis and 
metabolic syndrome. 
 
Risks/Discomforts 
We believe that this study does not involve significant risk for the volunteer subjects. The risks are 
anticipated to be greater than minimal, with the 7 day course of mifepristone too brief to offer the 
prospect of direct benefit to subjects.  The medical procedures include physical examination, non-
invasive tests (eg UFC and saliva collection), venipuncture and study agents with minimal side 


 
 
        IRB submission CR 11-16-17 
15 
effects at doses being used in the study. The risk: benefit ratio is low. The intravenous glucose 
tolerance test can be associated with greater than minimal risk, but these risks will be mitigated as 
noted below. 
1. Adrenal insufficiency can be associated with the use of mifepristone given its 
antiglucocorticoid action. In a previous subchronic study, Laue and colleagues found that 8 
of 11 healthy volunteers receiving mifepristone 10mg/kg/day for 7- 14 days exhibited 
generalized exanthem and one developed signs and symptoms of adrenal insufficiency.  In 
all cases symptoms resolved 5 - 6 days after discontinuation of mifepristone (44). In 
another study by Lambert et al, chronic daily treatment with 200 mg for months, 
mifepristone daily was associated with mild nausea and fatigue but no other signs and 
symptoms of adrenal insufficiency (45). However, given the short duration of 
administration and smaller doses of mifepristone being used in this study, these effects are 
unlikely. No adverse effects were reported after single or two-day doses of up to 400 mg in 
previous studies, or after 200 mg daily for 8 days (32, 33, 46). All subjects will be educated 
on the signs and symptoms of adrenal insufficiency and will be instructed to contact study 
personnel if they develop any such symptoms. Detailed history with regards to signs and 
symptoms of adrenal insufficiency will also be taken during the study visits. 
2. Hypoglycemia is a risk associated with the frequently sampled intravenous glucose 
tolerance test after insulin administration. The dose of insulin will be calculated 
meticulously and the test will be performed in a strictly monitored setting, with frequent 
measurement of glucose and the ability to administer additional glucose should 
hypoglycemia occur. Also, we believe that the risk of hypoglycemia with anticipated 
improvement in glucose intolerance on study drug in subjects on a stable dose of 
metformin is minimal. Glucose levels will however be monitored at every follow-up visit 
during the study. 
3. Deuterated isotopes used to evaluate cortisol and cortisone dynamics are not radioactive 
and are not expected to have adverse effects. 
4. Endometrial hyperplasia and vaginal bleeding is a theoretical risk with long-term 
administration of mifepristone. However, given the short duration of drug administration 
in this study we do not anticipate this effect. Postmenopausal women will be screened for 
pre-existing endometrial hyperplasia by ultrasound and any abnormal vaginal bleeding 
during the study will be investigated.  An MRI Pelvis will be performed if the transvaginal 
ultrasound is unable to provide an accurate measurement of the endometrial stripe. 
Subjects in whom a definite assessment of endometrial thickness cannot be made with 
either ultrasound or MRI (as may be the case in patients with multiple fibroids) will be 
followed closely for any abnormal vaginal bleeding and will undergo a repeat transvaginal 
ultrasound upon completion of the study.  
5. Phlebotomy is associated with mild discomfort and the possibility of bruising. There is a 
small risk of fainting, bleeding, or of infection. These will be minimized by placing the 
patient in a seated or supine posture and by the use of clean technique. 
6. Time involved in clinic visit and inpatient stay may be a discomfort. Every effort will be 
made to streamline the visits, and the amount of time required will be specified in the 
consent form as clearly as possible.  Women will be allowed to go out on pass when no 
testing is scheduled. 


 
 
        IRB submission CR 11-16-17 
16 
7. Anemia is a possible risk of phlebotomy. The total blood withdrawal over a six week period 
will be 425 ml which is within the NIH guideline of 450 ml for adults or 7ml/kg/6 weeks in 
all subjects. Every effort will be made to minimize the amount of blood drawn.   
8. Termination of pregnancy is possible with mifepristone.  Only non-pregnant women will be 
enrolled in the study. A pregnancy test will be obtained for all women at the screening visit 
and prior to study drug initiation. Women will be counseled regarding the risk of 
termination of pregnancy associated with study drug intake and will be asked to use non-
hormonal contraceptive methods if they are sexually active during the study and for one 
month after stopping the study medication. 
9. Hypokalemia has been seen with the use of mifepristone in Cushing’s syndrome. However, 
this is related to the significantly elevated cortisol levels seen in Cushing’s syndrome which 
overwhelm the 11BHSD2 enzyme leading to hypokalemia via its action at the 
mineralocorticoid receptor. Even if a compensatory rise in ACTH and cortisol level is seen 
with the low dose of mifepristone being used in this study, we do not anticipate the 
cortisol levels to go high enough to cause hypokalemia.  However, a comprehensive 
metabolic panel that will include a potassium level will be checked both at the post-
treatment visit (after 7 days of treatment with drug) as well as at the time of the safety visit 
(1 week after discontinuation of the study drug).  
10. MRI uses a strong magnetic field and radiowaves instead of x-rays and therefore does not 
have any associated risk of radiation exposure. Patients are at risk for injury from the MRI 
magnet if they have pacemakers or other implanted electrical devices, dental implants, 
aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including 
metal pins and rods, heart valves and cochlear implants), implanted delivery pump or 
shrapnel fragments. All subjects will be screened for these conditions prior to the study. 
Women of child bearing potential will have a pregnancy test performed before the MRI. 
Gadolinium-based contrast agents may be used with the MRI study. Subjects will be 
screened for any history of allergic reactions to these agents prior to administration. MRI 
evaluations may cause claustrophobia.  Should this occur the study will be stopped and re-
scheduled with administration of a sedative if needed. 
 
Subject Monitoring 
Detailed history will be obtained from the subjects both before and at the end of each 
treatment with regards to medication compliance and any side effects associated with the 
medication. The NICHD Data Safety and Monitoring Board (DSMB) will review lab results after the 
first 10 patients have completed the study, and any unanticipated adverse events.  Safety labs 
including comprehensive metabolic panel and complete blood count will be checked before and 
one week after each treatment. 
All serious adverse events occurring during the study, both patient-reported and those 
observed by the physician or nursing staffs will be recorded and reported to the regulatory 
agencies.  
 
Withdrawal Criteria 


 
 
        IRB submission CR 11-16-17 
17 
1. Pregnancy 
2. Inability to comply with study visits or requirements 
3. Serious adverse reaction to study medication 
4. Abnormal Vaginal bleeding 
5. Thromboembolic event or new onset condition requiring anticoagulation 
6. Subject withdraws informed consent 
 
Patients who develop a serious adverse reaction to the study medication will be evaluated and 
treated at the Clinical Center.  
 
 
Adverse Events and Protocol Violations and Deviations 
An adverse event is any unfavorable or unintended symptom, sign, or disease temporally 
associated with the use of the medication, whether or not it is considered to be related to the 
medication. The occurrence of adverse events will be sought by non-directed questioning of the 
subject at each study visit and by review of the menstrual and adverse event calendar. Adverse 
events can also be detected on physical examination and laboratory tests. Each adverse event will 
be evaluated with regards to its severity, relationship to study medication, duration, action taken, 
and clinical outcome in the subject.  
Serious adverse event or reaction will be defined as any untoward medical occurrence that 
at any medication dose or formulation causes death, is life-threatening, requires hospitalization, 
prolongs existing hospitalization, or results in significant disability. Medical judgment will be 
exercised in deciding whether expedited reporting is appropriate in case of medical events that 
may not be immediately life-threatening or require hospitalization but may require intervention to 
prevent such an outcome. All serious adverse events occurring during the study, both patient-
reported and those observed by the physician and nursing staff will be recorded and reported to 
the FDA within 10 days of our own notification.  Non-serious adverse events will be reported 
annually to the FDA. 
 
An unanticipated problem will be defined as any incident, experience, or outcome 
that is unexpected, related/possibly related to participation in the study and suggests that 
the research places subjects or others at a greater risk of harm than was previously known 
or recognized. These events will be reported to the IRB and Clinical Director within 7 
(serious) or 14 (non-serious) days.   
 
 
Protocol violations and deviations will be reported to the IRB, except for the 
following: The protocol involves several serial tests, some with blood draws over 24 hours. 
Every effort is made to ensure that the subject has a reliable IV access prior to initiation of 
study procedures and the IV line is flushed intermittently to maintain access. However, we 
anticipate that blood draws may still be missed or delayed due to IV access issues ~10% of 
the time. We will monitor and keep a record of these but will report it as a protocol 
deviation to the IRB only if this happens > 10% of the time.  
 
 
HUMAN SUBJECTS PROTECTION 
 
Gender, ethnicity and age considerations for subject selection:   


 
 
        IRB submission CR 11-16-17 
18 
This study will focus on men and women of all ethnicities in the age group of 35 – 70 years. We 
have no reason to believe that the effect of treatment with mifepristone will be different based on 
gender or ethnicity.  
 
Recruitment strategies: Subjects will be obtained through referrals from individuals studied under 
the NIDDK phenotyping protocol 07-DK-0077, and may be employees. Subjects may also be 
recruited through a variety of other mechanisms, including but not limited to bulletin board 
postings, the Human subjects volunteer program, listing in the NIH record, mailings to physicians, 
advertisements in local newspapers, posting messages on listserves, social networking sites (like 
facebook and twitter), local online classified pages (like Craigslist) and via the clinical center web 
page. We will submit these postings and proposed language to the IRB for approval.  If employees 
are recruited, they will receive the NIH Information Sheet on Staff Research Participation per NIH 
HRPP SOP 14E, Research Involving NIH Staff as Subjects.  Every effort will be made to ensure 
confidentiality of collected information; we do not anticipate a need to collect sensitive 
information such as sexual behavior, or HIV status.  Consent will be obtained as outlined in SOP 
14E. 
 
 
Consent Procedures: The Patient Recruitment and Patient Liaison group will initially screen 
potential subjects.  The research team will call subjects for further screening, provide the consent 
form, and offer participation.  The study will be explained verbally and all questions and concerns 
addressed by phone conversation and at the first visit.  This telephone call will be used to explore 
eligibility for participation, as well as feasibility, given the time commitment, and whether the 
subject is able to travel to NIH. 
 
Written informed consent will be obtained from the participant prior to any study procedures or 
treatments. The Principal Investigator and other designated qualified protocol investigators (listed 
on the protocol’s face page) are clinically trained and have experience in obtaining informed 
consent, and know the protocol very well.  The informed consent process and protections (e.g. 
lack of coercion) will be carried out as per NIH HRPP  SOP 12, Requirements for Informed Consent. 
 
We do not plan or anticipate the enrollment of non-English speaking subjects; however they are 
not excluded from participation either. Should a non-English speaking subject be eligible for 
enrollment, IRB approval will be obtained for use of the short form consent process in the absence 
of a fully translated consent document as outlined in SOP 12.9.1, under the provisions of 45 CFR 
46.117(b)(2). IRB approval will be obtained according to IRB guidance prior to obtaining informed 
consent from the potential study participant/s. 
 
CONFIDENTIALITY AND USE OF RETAINED SPECIMENS 
 
Study subjects will be informed at the time of consent that the investigators will not 
provide direct care or counseling for conditions revealed by physical exam or protocol test results, 
but that the subject will be referred appropriately for further medical evaluation and treatment of 
any abnormal findings.  
 
Samples will be stored according to NICHD and NIH policy in the NICHD biorepository 
(serum/plasma/urine). Subjects will be asked if samples obtained during the study can be used in 


 
 
        IRB submission CR 11-16-17 
19 
the future, for studies not described here without obtaining new informed consent. Only studies 
related to the physiology of the HPA axis will be undertaken. Blood samples may be shared with 
collaborators, without personal identifiers.  
 
REMUNERATION OF SUBJECTS 
 
Subjects will be taking an investigational drug and will have the inconvenience of travel to 
the NIH for study visits.  Thus we propose to remunerate subjects for participation according to 
NIH guidelines. As recommended, inconvenience units will be used for invasive or non-standard 
procedures that would not be included in routine physical examination.  The reimbursement 
amount based on mandatory NIH compensation for inpatient and outpatient visits will be as 
follows: 12 inpatient visit days (12 x $40 = $480), 2 outpatient visits lasting > 1 hour – screening 
visit and transvaginal ultrasound ($30 x 2 = $60) and 4 outpatient safety visits lasting < 1 hour 
duration ($20 x 4 = $80). Thus according to the mandated NIH compensation, they would receive 
$620. Additional compensation of $60 ($40 + $20) will be given to subjects who undergo an MRI 
Pelvis when the endometrial thickness cannot be assessed precisely on the transvaginal ultrasound 
(as in the presence of multiple fibroids).  Inconvenience units will be assigned as follows: 
Investigational drug (4 units = $40), 12 days of multiple blood sampling (1 unit x 12 = $120), and 4 
days of outpatient blood draws (2 units = $20) and a completion bonus of $100. Thus, total 
compensation would be up to $960 for those who complete the study.  
 
We also propose to provide travel compensation for all subjects, either metro fare or 
mileage.   
 
 
OTHER INTERESTED PARTIES AND COLLABORATORS 
The NIH has a Cooperative Research and Development Agreement (CRADA) with 
Laboratoire HRA-Pharma, in Paris, France.  The intention of the CRADA is to develop mifepristone 
for the treatment of Cushing’s syndrome, for use as an adjunctive agent for Octreoscan, and for 
use as a diagnostic agent.  
 
 
 
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hydroxysteroid dehydrogenase type 1 expression and elevated hepatic 5alpha-reductase 
activity. Diabetes 57:2652-2660 
25. 
Vassiliadi DA, Barber TM, Hughes BA, McCarthy MI, Wass JA, Franks S, Nightingale P, 
Tomlinson JW, Arlt W, Stewart PM. 2009 Increased 5 alpha-reductase activity and 
adrenocortical drive in women with polycystic ovary syndrome. J Clin Endocrinol Metab 
94:3558-3566 
26. 
Liu Y, Nakagawa Y, Wang Y, Sakurai R, Tripathi PV, Lutfy K, Friedman TC. 2005 Increased 
glucocorticoid receptor and 11{beta}-hydroxysteroid dehydrogenase type 1 expression in 
hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice. Diabetes 
54:32-40 
27.  
Taylor AI, Frizzell N, McKillop AM, Flatt PR, Gault VA. 2009 Effect of RU486 on hepatic and 
adipocyte gene expression improves diabetes control in obesity-type 2 diabetes. Horm 
Metab Res 41:899-904 
28. 
Langley SC, York DA. 1990 Effects of antiglucocorticoid RU486 on development of obesity 
in obese fa/fa Zucker rats. Am J Phsiol 259:R539-544 
29. 
Okada S, York DA, Bray GA. 1992 Mifepristone (RU486), a blocker of type II glucocorticoid 
and progestin receptors, reverses a dietary form of obesity. Am J Physiol 262:R1106-R1110 
30. 
Nieman LK, Chrousos GP, Kellner C, Spitz IM, Nisula BC, Cutler GB, Merriam GR, Bardin 
CW, Loriaux DL. 1985 Successful treatment of Cushing’s syndrome with the glucocorticoid 
antagonist RU 486. J Clin Endocrinol Metab 61:536-540 
31. 
FDA News Release: FDA approves Korlym for patients with endogenous Cushing’s 
syndrome. 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm292462.htm 
32. 
Ottosson M, Marin P, Karason K, Elander A, Bjorntorp P. 1995 Blockade of the 
glucocorticoid receptor with ru 486: Effects in vitro and in vivo on human adipose tissue 
lipoprotein lipase activity. Obes Res 3:233-240 
33. 
Bertagna X, Bertagna C, Luton JP, Husson JM, Girard F. 1984 The new steroid analog 
RU486 inhibits glucocorticoid action in man. J Clin Endocrinol Metab 59:25-28 
 


 
 
        IRB submission CR 11-16-17 
22 
34. 
Standards of medical care in Diabetes – 2011. Diabetes Care January 2011 34:S11-
S61; doi:10.2337/dc11-S01142 
35. 
Kroenke K, Spitzer RL, Williams JB. 2001 The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med 16(9):606-13 
36. 
National Institute of Health; National Heart, Lung, and Blood Institute. Joint National 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 
North American Association for the Study of Obesity.The Practical Guide: Identification, 
Evaluation, and Treatment of Overweight and Obesity in Adults. NIH: Bethesda, MD, 2000. 
37. 
Ben-Noun L, Sohar E, Laor A. 2001 Neck circumference as a simple screening measure for 
identifying overweight and obese patients. Obes Res 9(8): 470-7 
38. 
Muniyappa R, Lee S, Chen H, Quon MJ. 2008 Current approaches for assessing insulin 
sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J 
Physiol Endocrinol Metab 294:E15-E26 
39. 
Chow CC, Periwal V, Csako G, Ricks M, Courville AB, Miller BV, Vega GL, Sumner AE. 2011 
Higher acute insulin response to glucose may determine greater free fatty acid clearance in 
African-American women. J Clin Endocrinol Metab 96 (8): 0000-0000 epub 
(doi:10.1210/jc2011-0532 
40. 
Andrew R, Smith K, Jones GC, Walker BR. 2002 Distinguishing the activities of 11beta-
hydroxysteroid dehydrogenases in vivo using isotopically labeled cortisol. J Clin Endocrinol 
Metab 87(1):277-85 
41. 
Kettel LM, Murphy AA, Mortola JF, Liu JH, Ulmann A, Yen SS.  1991 Endocrine responses 
to long-term administration of the antiprogesterone RU486 in patients with pelvic 
endometriosis. Fertil Steril. 56(3):402-7 
42. 
Bertagna X. 1997 Pituitary-adrenal response to RU486 in man. Psychoneuroendocrinology 
22 Suppl 1:S51-5. 
43. 
Donaldson K, Briggs J, McMaster D. 1994 RU486: An alternative to surgical abortion. J 
Obstet Gynecol Neonatal Nurs 23(7):555-9 
44. 
Laue L, Lotze MT, Chrousos GP, et al. 1990 Effect of chronic treatment with the 
glucocorticoid antagonist RU486 in man: toxicity, immunological, and hormonal aspects. J 
Clin Endocrinol Metab 71(6):1474-80 
45. 
Lamberts SWJ, Koper JW, de Jong FH. 1991 The endocrine effects of long-term treatment 
with mifepristone (RU486). J Clin Endocrinol Metab 73(1):187-91 
46.  
Bertagna X, Escourolle H, Pinquier JL, Coste J, Raux-Demay MC, Perles P, Silvestre L, Luton 
JP, Strauch G. 1994  Administration of RU 486 for 8 days in normal volunteers: 
antiglucocorticoid effect with no evidence of peripheral cortisol deprivation. J Clin 
Endocrinol Metab 78:375-80. 
 
 

ICF_001.pdf: 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Institute of Child Health and Human Development 
 
 
STUDY NUMBER: 
11-CH-0208 
PRINCIPAL INVESTIGATOR:  Lynnette Nieman, M.D. 
 
 
STUDY TITLE: 
Effects of the Glucocorticoid Antagonist, Mifepristone, on Glucose Intolerance in Obese and 
Overweight Individuals  
 
 
Continuing Review Approved by the IRB on 11/29/16 
Amendment Approved by the IRB on 12/16/15 (Q) 
 
 
Date Posted to Web:   12/17/16 
Standard 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional.
 
 
Nature of the Study 
Cortisol, a hormone produced by the adrenal glands, is an important regulator of metabolism.  Blood levels of cortisol have a 
natural day-to-night pattern so that the highest levels occur in the morning and lowest levels at night. This diurnal rhythm is 
maintained by a normal “feedback” so that the body recognizes when there is enough cortisol and turns off production and 
when levels get low, cortisol production is switched back on.  The switch that increases cortisol is a hormone called ACTH, 
which is made by the pituitary gland located at the base of the brain.  ACTH levels increase or decrease to cause the 
changes in cortisol secretion. 
 
Some studies have shown that individuals with central obesity and insulin resistance have higher than normal cortisol levels 
(either in the blood or at the tissue level), lose the natural diurnal rhythm, and have abnormal dynamic cortisol tests. It is 
therefore thought that cortisol abnormalities may play an important role in the development of glucose intolerance and 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-CH-0208 
CONTINUATION:  page  2  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
insulin resistance.  
 
Mifepristone is a drug that blocks the actions of cortisol in the body. This study is designed to better understand the role of 
cortisol in the development of glucose intolerance.  
 
Study Design 
 
Your Involvement 
We invite you to participate in this study if you are between the ages of 35 to 70 years are overweight or obese, and have 
abnormal glucose levels.   You may not enter the study if you have conditions that may affect the study results. This 
includes use of estrogen therapy, use of medications for treatment of diabetes, sleep disorders, certain psychiatric disorders, 
severe kidney, liver or heart problems, known history of infection with human immunodeficiency virus (HIV) and history of 
cancer of the uterus or unexplained vaginal bleeding.  
 
Screening Visit 
Potential participants first will be seen at the Clinical Center to assess if they may enter the study.  This will include 
measurement of height, weight, waist and hip circumference, blood pressure, electrocardiogram (heart rhythm tracing) and 
a history and physical examination. After an overnight fast, blood will be drawn for glucose, hormone levels to assess for 
postmenopausal state, and other basic blood tests to examine your general health status. Women will also undergo a 
transvaginal ultrasound test to look at the thickness of the lining of their uterus and will have a blood pregnancy test.  
A magnetic resonance imaging (MRI) scan will be performed ONLY IF the transvaginal ultrasound is unable to provide an 
accurate measurement of the thickness of the lining of the uterus. MRI uses a strong magnetic field and radiowaves instead 
of x-rays to obtain images of body organs and tissues. Since x-rays are not used, there is no risk of radiation exposure. The 
MRI scanner is a metal cylinder surrounded by a strong magnetic field. During the MRI, you will lie still on a table that can 
slide in and out of the cylinder. Scanning time may vary from 20 minutes to an hour. Individuals with fear of confined 
spaces may become anxious during this procedure. You will be able to communicate with the MRI staff at all times during 
your scan, and you may ask to be moved out of the machine at anytime. As part of the MRI study, you may receive a 
contrast agent into your vein that is gadolinium-based. These agents are approved by the FDA for use with MRI imaging.  
An oral glucose tolerance test also will be performed at the screening visit in the morning after a 12-hour fast.  As part of 
this test, you will be asked to drink a sweet beverage over a 5 minute period and blood samples will be drawn from an 
intravenous catheter (IV) placed in your arm.  The results of the test will tell us how high your blood sugar levels go and this 
will be used to make the diagnosis of pre-diabetes and diabetes.  Some people do not like the sweetness of the beverage 
and may feel nauseated.   
 
Individuals who are eligible for the study will continue with the visits below.  Women will have a blood pregnancy test 1 – 2 
days before initiation of testing at each admission.  Only women with a negative result will continue in the study. 
 
Study Outline 
The study involves testing before and after seven days of treatment with each of two study medications - placebo every 6 
hours or mifepristone 50 mg every 6 hours. Each person will take both the placebo and mifepristone treatments, but you will 
not be told which treatment you are receiving and you will undergo each treatment only once.  As a result you will be 
studied on each of the two treatment arms exactly once in a random order.  
 
Each treatment involves 3 days of baseline testing before beginning the study drug, then seven days of treatment with the 
study drug, followed by 3 days of post-treatment testing. There will be a gap of at least six and no more than eight weeks 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-CH-0208 
CONTINUATION:  page  3  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
between the two treatments and therefore the total duration for the study will be at least nine weeks.  You will be asked not 
to start on any new diet or exercise regimen during the entire study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Procedures 
 
For each treatment, you will be admitted to the 5SWN metabolic unit in the Clinical Center on a Sunday for testing to begin 
the following day.  
 
Day 1 (Monday): Body Measurements, blood drawing for glucose, cortisol and ACTH, 24 hour urine 
Height, weight, waist, hip and neck circumference and blood pressure (mean of three measurements) will be recorded. 
Blood pressure will be measured after you have been laying down for at least 5 minutes. You will be asked to not smoke or 
drink caffeine (found in coffee, tea and some soft drinks) for 30 minutes before the blood pressure measurement.  After a 
morning fasting blood draw, an IV will be inserted into a vein in the arm at 8 am. We will be using this IV line to draw blood 
every hour from 9 AM on Monday to 9 AM on Tuesday for measurement of cortisol and ACTH levels. During this 24 hours of 
blood draws, you can choose to sit or lay down. You may get up at any point to use the bathroom. You will be allowed to 
use a computer or watch TV if the programs will not stress or excite you too much. Getting either too excited or stressed 
can affect the cortisol levels that will be studied. A 24 hour urine collection for measurement of cortisol and its break down 
products will also be done on the same day. Blood will also be drawn before and two hours after breakfast, lunch and dinner 
for glucose measurements.  You will be allowed to take water, but no food or drinks with calories after 8 PM. 
 
Day 2 (Tuesday):  Testing for how the body reacts to intravenous glucose and insulin  
After finishing the 24 hour urine collection and the hourly blood draws, you will undergo a frequently sampled intravenous 
glucose tolerance test (FSIVGTT).  This test will help us find out how your body reacts to insulin.   In the morning, two IVs 
will be placed, one in each arm.  At the start of the test, glucose will be given to you through the IV over one to two 
minutes.  Twenty minutes later, a small dose of insulin will be given through the IV.  You will be monitored very carefully 
while blood samples are taken for the next three hours. The risks from this test include the possibility of slight arm 
tenderness during the glucose infusion, flushing and mild nausea during the glucose infusion and low blood glucose levels 
after the insulin is given.  With low blood glucose, people may get hungry, have a headache, feel shaky or dizzy or may 
sweat or become drowsy. If low blood glucose does occur, the test will be stopped and you will be given juice or glucose by 
vein to raise the blood glucose to normal. After completion of the intravenous glucose tolerance test, you will be allowed to 
go on pass if you can return the next morning by 8 AM. 
 
Day 3 (Wednesday): Testing for how body reacts to glucose load by mouth  
Randomized to Placebo 
Screening 
visit 
Treatment Period 1 
Treatment Period 2 
Safety visit- Day 19 & 33 
6 – 8 week washout 
Randomized to Mifepristone 
Randomized to Mifepristone 
Randomized to Placebo 
Day 1                      Day 12   
Day 1                   Day 12  
Safety visit 
- Day19 & 
33
Figure 1: Study Design Overview 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-CH-0208 
CONTINUATION:  page  4  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
A 3-hour 75-gram oral glucose tolerance test, as described earlier, with blood draws every 30 minutes will be performed on 
the third day of testing before and after the study drug. 
 
After the conclusion of the day 3 study, you will be provided with the study drug and allowed to go out on pass with 
instructions to begin taking the study drug at 6 PM, and continue to take it every 6-hours (midnight, 6AM, noon and 6PM). 
 
Day 4 – 9 (Thursday – Tuesday): You will continue taking the study drug as instructed for seven days and will return to the 
5SWN metabolic unit for admission on day 9 of the study (Tuesday), bringing the remaining study medication and the pill 
bottles with you. 
 
Day 10– 12  (Wednesday-Friday): After an overnight fast, all study procedures indicated for day 1 - 3 will be repeated on 
day 10 - 12. You will continue taking the study drug until the completion of all study procedures on day 12.  
 
Day 19 and 33 (± 5 days):  Approximately one week and then three weeks after the last day of study drug intake, you will 
return for follow-up safety visits where you will undergo a brief history and physical exam and blood will be drawn for 
measurement of blood chemistries and blood counts.   
 
These study procedures will be repeated for the second treatment after a gap of 6-8 weeks. The pre-study drug testing 
(Days 1 through 3) for each treatment can be done on days other than as specified above as long as it is done no more 
than 10 days before you start taking the study medication. 
 
 
Testing for how cortisol is handled by the body 
This study will be performed only once during the study- at least one and no more than two months after completion of the 
second treatment arm. An IV will be placed for blood drawing to measure 11-beta hydroxysteroid dehydrogenase (11BHSD) 
activity. 11BHSD is an enzyme that changes cortisol to active and inactive forms. After placement of the IV line, we will give 
a bolus dose followed by continuous infusion of deuterated (deuterium labeled) cortisol for a period of 3 hours and 20 
minutes. During this time we will draw blood every 60 minutes for 3 hours and then every 5 minutes for 20 minutes to 
measure the change of the labeled cortisol into inactive and active forms. The deuterated isotope of cortisol is not 
radioactive and there are no additional side-effects other than those associated with placement of an IV. 
 
 
Medications Used in the Study 
Mifepristone is a drug that blocks the action of cortisol in the body.  By blocking glucocorticoid action it can increase cortisol 
levels. High daily doses of mifepristone have been used safely to treat a few subjects with tumors causing excessive cortisol 
production as well as certain kinds of cancer, gynecological diseases, and psychiatric disorders.  No major safety issues have 
been raised from these clinical studies.  Mifepristone has been used safely in many countries for more than ten years at a 
single dose of 600 mg to terminate early pregnancy as well as for induction of labor at term. Women who have not 
undergone menopause and can become pregnant will be asked to use a non-hormonal contraceptive method if they are 
sexually active during the study and for one month after stopping the study medication.  
 
 
 
Alternatives to Participation in this Study and Rights Upon Refusal or Withdrawal From this Study 
The choice to enter or not enter this study is entirely voluntary.  Before you make a decision to enter or not, you should 
understand what the doctor has explained and what you have read about the research study.  If you decide not to 
participate, your enrollment in any other protocol will not be affected.  If you are not sure that you wish to participate in this 
study, let us know at any time.  You are free to withdraw from the study at any time.  This study is not intended to be a 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-CH-0208 
CONTINUATION:  page  5  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
long-term treatment of metabolic syndrome or diabetes. The usual treatments for metabolic syndrome and diabetes include 
lifestyle changes with diet and exercise as well as medications to lower blood sugar levels like metformin and insulin. 
 
Risks and Discomforts 
Most procedures of the study, such as blood drawing, urine collection, and an oral glucose tolerance test represent basic 
medical interventions with some discomfort and minimal risk while the intravenous glucose tolerance test is associated with 
greater than minimal risk. Mifepristone is an experimental agent with minimal side-effects at doses being used in the study. 
 
1. Phlebotomy may cause bruising and there is a small chance of fainting, infection, or inflammation of the vein. These will 
be minimized using a clean technique and by placing you in a seated or lying position.  
2. Hypoglycemia or a low blood sugar level can be associated with insulin administration used in the intravenous glucose 
tolerance test. The dose of insulin will be calculated carefully to reduce this risk and the test will be performed in strictly 
monitored setting.  If a low blood sugar develops you will be treated to increase the blood sugar. 
3. Anemia is a possible risk of phlebotomy. No more than 425 ml of blood will be taken over a 6 week period and 
therefore it is unlikely that you will develop a low blood count because of the study. 
4.  Discomfort associated with transvaginal ultrasound. Insertion of the ultrasound vaginal probe is usually well tolerated 
but occasionally may be uncomfortable. The sound waves from the ultrasound machine are painless and do not pose a 
medical hazard to you. 
5. Mifepristone administration, at the doses and time period used in the study, has minimal risk. Long-term side-effects 
may include adrenal insufficiency, endometrial thickening and vaginal bleeding; however this study does not include 
chronic use. Termination of pregnancy is a risk associated with mifepristone.  A pregnancy test will be performed prior 
to participation in the study. Women who have not undergone menopause and can become pregnant will be asked to 
use a non-hormonal contraceptive method if they are sexually active during the study and for one month after stopping 
the study medication. 
6. Risks associated with an MRI scan if performed:  
MRI uses a strong magnetic field and radiowaves instead of x-rays and therefore is not associated with any risk of 
radiation exposure.  
Patients are at risk for injury from the MRI magnet if they have pacemakers or other implanted electrical devices, dental 
implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, 
heart valves and cochlear implants), implanted delivery pump or shrapnel fragments. Welders and metal workers may 
also be at risk for injury because of possible small fragments in the eye which they may be unaware of. You will be 
screened for these conditions prior to the study, and if you have any of these conditions, you will not receive an MRI 
scan. If you have a question about any metal objects being present in your body, you should inform the physician. In 
addition all magnetic objects (for example, watches, coins, jewellery, credit cards) must be removed before entering the 
MRI scan room. All women of child bearing potential will have a pregnancy test performed which must be negative 
before proceeding with the MRI. You will be asked to complete an MRI screening form, and to sign a separate MRI 
consent form. 
Gadolinium-based contrast agents are approved by the FDA for use with MRI imaging. The vast majority of patients 
receiving gadolinium-based contrast agents have no symptoms related to the injection of this medication. Mild 
symptoms that may occur include coldness in the arm at the time of injection, a metallic taste, headache and nausea. In 
an extremely small number of patients, more severe symptoms have been reported including shortness of breath, 
wheezing, hives, and lowering of blood pressure. You should not receive gadolinium-based contrast agents if you 
previously had an allergic reaction to them and will be asked about this before administration of any contrast agents.  


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-CH-0208 
CONTINUATION:  page  6  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
7. Tests conducted during this study may uncover a medical condition that could affect your health in the future.  Any 
illness that we detect during these tests will be discussed with you. If a condition is discovered that prevents your 
participation in this study, you will not be eligible for treatment of that condition under this protocol.  However, records 
of tests obtained during the screening may be forwarded to a physician of your choice to help further evaluation and 
treatment. 
 
Benefits 
You may benefit personally by undergoing a basic physical examination and basic blood tests. In addition, this study will 
contribute to our current understanding of the role of cortisol and the pathophysiology of metabolic syndrome and may lead 
to development of treatment modalities for various components of metabolic syndrome.  
 
Remuneration 
You will be taking an investigational drug for a short period of time and will have the inconvenience of travel to the NIH for 
study visits. Thus we propose to remunerate you for participation according to NIH guidelines. As recommended, we will be 
paying according to the level of inconvenience of the study procedures. We will take into account the fact that you will be 
undergoing: multiple blood draws, urine collection, brief hospital stay, and drug administration. The total compensation 
would be $900 if you complete the study.  
 
Confidentiality and Use of Retained Tissue Specimens 
We will record your name with your blood and urine specimen.  Initially, these samples will be used as described above for 
studies at the NIH.  Additionally, the samples could be stored for a long time, with your name, and used for different studies 
than those we originally plan.  For example, if we discover new effects of cortisol on a protein in the blood, we may 
evaluate that effect in your stored samples.  However, such studies would be limited to evaluation of the effects of cortisol 
and/or mifepristone.  The researchers conducting these studies will not contact you for more information. These future 
studies will not benefit you personally, and are not needed for your medical care. If you decide in the future that you no 
longer want your sample to be used for research, please contact the study doctors and any remaining sample will be 
destroyed. Please indicate your preference regarding future use of your samples by initialing one of the choices below. 
 
 
_________These samples may be 
used for future studies related to 
cortisol and/or mifepristone 
 
 
 
______I agree that my blood may  
be used in future studies for other  
conditions if I am contacted in  
advance and can rescind this 
authorization if I choose. 
 
 
________ Under no circumstances 
should these samples be used for 
future studies.  Samples should be 
discarded once the present study is 
complete. 
 
 
If you agree to possible future use of the samples, it is possible that those studies may involve sharing your samples with 
other investigators.  If this is done, information about your medical condition may also be shared for the purpose of the 
future study.  Information about you would be sent with a coded identification so that your name would not be linked to the 
information received by the other investigators.  These studies would only involve investigations related to cortisol. 
 
Your medical records are kept confidential to the extent allowable by law.  Results of tests performed with the blood 
obtained from you will be kept confidential.  However, access to your records will be allowed to individuals carrying out this 
study, so that appropriate information can be collected and possibly published in scientific journals. 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-CH-0208 
CONTINUATION:  page  7  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
The results of research tests performed with the blood obtained will not routinely be provided to you.  By agreeing to 
participate in this study you do not waive any rights that you may have regarding access to and disclosure of your records. 
 
Other Interested Parties and Collaborators 
The NIH has a Cooperative Research and Development Agreement (CRADA) with Laboratoire HRA Pharma, 15 rue Béranger, 
75003 Paris, France to develop mifepristone through a joint study with the company. This means it is possible that the 
results of this study could lead to payments to NIH scientists and to the NIH. By law, government scientists are required to 
receive such payments for their inventions. You will not receive any money from the development of mifepristone. As part of 
this CRADA, HRA Pharma supplies the mifepristone for this study. 
 
 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
11-CH-0208 
CONTINUATION:  page  8  of  8  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital 
accreditation organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health.  Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal Investigator, Dr. Lynnette Nieman, Bldg 
10/CRC, Room 1-3140, Telephone: 301-496-5800. You may also call the Clinical Center Patient Representative at 301-
496-2626. 
 
5. Consent Document.  The consent form has been signed and a copy has been given to the patient. Please keep a 
copy of this document in case you want to read it again. 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM NOVEMBER 29, 2016 THROUGH NOVEMBER 28, 2017. 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name