Effects of the Glucocorticoid Antagonist, Mifepristone, on Glucose Intolerance in Obese and Overweight Individuals
Phase: PHASE1
Conditions: Endocrine Disease, Diabetes
Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

 
 
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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 

 
 
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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. 

 
 
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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 

 
 
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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 

 
 
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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 

 
 
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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 

 
 
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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 

 
 
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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 

 
 
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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 

 
 
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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.  

 
 
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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. 

 
 
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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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