Mifepristone Dynamic Testing for Diagnosis for Central Adrenal Insufficiency
Phase: PHASE2
Conditions: Central Adrenal Insufficiency, Mifepristone
Sponsor: Tobias Else

 
 
Mifepristone Dynamic Testing for 
Diagnosis for Central Adrenal 
Insufficiency 
 
 
NCT04588688 
 
 
IRB Approval Date: March 18, 2020 
 
 
 

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CLINICAL PROTOCOL  
Mifepristone Dynamic Testing for Diagnosis for Central Adrenal 
Insufficiency 
 
 
 
Study Agents: Mifepristone 
 
 
 
HUM #: 00160641 
 
IND #: 146278 
 
Sponsor Investigator: Tobias Else, Assistant Professor, Department of Internal 
Medicine 
 
Institution: University of Michigan 
 
Version 1.5, February 17th, 2020 
 
 

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Table of Contents 
TABLE OF CONTENTS .................................................................................................. 3 
LIST OF TABLES ............................................................................................................. 4 
PROTOCOL SYNOPSIS .................................................................................................. 5 
1 
INTRODUCTION ...................................................................................................... 7 
1.1 
INDICATION ........................................................................................................ 7 
1.2 
BACKGROUND AND RATIONALE ................................................................. 7 
1.3 
HYPOTHESIS ....................................................................................................... 9 
1.4 
PREVIOUS HUMAN EXPERIENCE ................................................................. 9 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................... 10 
2.1 
OBJECTIVES ...................................................................................................... 10 
2.2 
ENDPOINTS ........................................................................................................ 11 
2.2.1 
PRIMARY ENDPOINT ................................................................................ 11 
2.2.2 
SECONDARY ENDPOINT .......................................................................... 11 
2.2.3 
EXPLORATORY ENDPOINTS .................................................................. 11 
3 
STUDY DESIGN ...................................................................................................... 13 
4 
SUBJECT SELECTION .......................................................................................... 14 
4.1 
SUBJECT RECRUITMENT .............................................................................. 14 
4.1.1 
INCLUSION CRITERIA .............................................................................. 14 
4.1.2 
EXCLUSION CRITERIA............................................................................. 14 
5 
STUDY TREATMENTS.......................................................................................... 16 
5.1 
ALLOCATION TO TREATMENT .................................................................. 16 
5.2 
BREAKING THE BLIND .................................................................................. 16 
5.3 
DRUG SUPPLIES-MIFEPRISTONE ............................................................... 16 
5.4 
CONCOMITANT MEDICATIONS .................................................................. 19 
6 
STUDY PROCEDURES- SEE THE SCHEDULE OF ACTIVITIES ................. 19 
6.1 
SCREENING VISIT ............................................................................................ 19 
6.2 
TREATMENT STUDY PERIOD ...................................................................... 19 
6.2.1 
VISIT 1 (DAY 1) ............................................................................................ 19 
6.2.2 
FOLLOW-UP ................................................................................................. 20 
6.2.3 
SUBJECTS WITH HISTORY OF ADRENAL INSUFFICIENCY ......... 20 
7 
ASSESSMENTS ....................................................................................................... 23 
7.1 
PRIMARY ENDPOINT ASSESSMENTS ........................................................ 23 
7.2 
SECONDARY ASSESSMENTS ........................................................................ 23 
7.3 
EXPLORATORY ASSESSMENTS................................................................... 23 
8 
ADVERSE EVENT REPORTING ......................................................................... 24 
8.1 
ADVERSE EVENT DEFINITION .................................................................... 24 
8.2 
EVENT REPORTING: ....................................................................................... 27 
8.2.1 
SERIOUS ADVERSE EVENT REPORTING GUIDELINES.................. 27 
8.2.2 
ROUTINE REPORTING ............................................................................. 28 
9 
DATA ANALYSIS/STATISTICAL METHODS .................................................. 28 
9.1 
SAMPLE SIZE DETERMINATION ................................................................ 28 
9.2 
DATA ANALYSIS ............................................................................................... 28 
9.2.1 
ANALYSIS POPULATIONS ....................................................................... 28 
9.2.2 
ANALYSIS OF PRIMARY ENDPOINT .................................................... 29 
9.2.3 
ANALYSIS OF SECONDARY ENDPOINTS ............................................ 29 

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9.2.4 
ANALYSIS OF SECONDARY ENDPOINTS ............................................ 30 
10 MONITORING ......................................................................................................... 31 
11 DATA HANDLING AND RECORD KEEPING .................................................. 31 
11.1 
CRFS / ELECTRONIC DATA RECORD ........................................................ 31 
11.2 
RECORD RETENTION ..................................................................................... 32 
12 ETHICS ..................................................................................................................... 33 
12.1 
IRB/FDA ............................................................................................................... 33 
12.2 
INSTITUTIONAL REVIEW BOARD (IRB) ................................................... 33 
12.3 
SUBJECT INFORMATION AND CONSENT................................................. 33 
12.4 
STUDY DISCONTINUATION CRITERIA ..................................................... 34 
12.4.1 
STOPPING RULES FOR SAFETY REASONS ........................................ 34 
12.4.2 
RULES FOR DISCONTINUATION OF A SUBJECT ............................. 34 
13 REFERENCES ......................................................................................................... 35 
 
List of Tables 
Table 1.  
Schedule of Activities ............................................................................... 22 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
 
Financial Sponsor: Corcept Therapeutics, Inc. 
Name of Finished Product: Mifepristone (Korlym)  
Study Title: Mifepristone Dynamic Testing for Diagnosis for Central Adrenal 
Insufficiency 
Study Phase: Phase II 
Primary Objective: Phase I of the study is to determine whether recruitment at 
our institution is sufficient for a study for mifepristone use as a diagnostic tool to 
diagnose central adrenal insufficiency and to generate data to inform a post-pilot 
study. Phase II of the study involves taking those recruited and having them 
complete the study to generate the data.  
Study Design: Single-center pilot feasibility study of mifepristone to evaluate the 
recruitment of participants with the diagnosis of confirmed or suspected 
secondary adrenal insufficiency.  
Cortisol (secondary endpoint), ACTH and other steroid responses (exploratory 
endpoints) to mifepristone in participants with normal insulin tolerance testing 
(ITT) and participants with confirmed or suspected adrenal insufficiency will be 
analyzed.  
The study will test primarily for feasibility of recruitment (phase 1) and provide 
preliminary data for planning a post-pilot study (phase 2).  
Study Population: Subjects with normal ITT and subjects with confirmed or 
suspected diagnosis of central adrenal insufficiency. 
1. Criteria for Inclusion and Exclusion: Please see section 4.  
 
Test Product; Dose; and Mode of Administration: Single dose of mifepristone 
600mg, administered orally  
 
Reference or Placebo Therapy; Dose; and Mode of Administration: None 
Duration of Treatment: One day 
Variables: Cortisol, ACTH 

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Statistical Methods:  
- For the primary endpoint of recruitment actual recruitment will be compared to 
target recruitment (1 patient per 6 weeks). Actual and target recruitment per month 
will be plotted and visually compared. Recruitment of ≥ 26 participants and study 
completion and complete data on ≥ 22 patients will be a success regarding the 
primary endpoint. 
- For the secondary endpoint the day 2 cortisol level will be compared to the 
maximal ITT cortisol level to determine if and to what degree there is a correlation 
between the two measurements.  
- Receiver operating characteristic (ROC) curve will be created with the day 2 
cortisol level as the variable, and the ITT result as the “gold standard” test for 
adrenal insufficiency, to analyze the performance of cortisol as a diagnostic test. 
- T-tests will be used to compare cortisol, ACTH, and other hormone levels 
between healthy individuals and those with diagnosed with central adrenal 
insufficiency. 
 
 

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1 INTRODUCTION 
1.1 
Indication 
Central adrenal insufficiency (CAI) is the inadequate production of cortisol in the 
setting of physiologic stress. In contrast to primary adrenal insufficiency, CAI is due 
to pituitary or hypothalamic dysfunction. Today, CAI has a prevalence of roughly 
150-280 per million.i The most common cause of CAI is administration of 
exogenous glucocorticoids. Other common pharmacologic causes of CAI include 
synthetic progestins and opiates, which can suppress the hypothalamic-pituitary-
adrenal (HPA) axis. Primary pituitary pathologies include tumors, congenital or 
developmental causes, and hypophysitis. Brain trauma, radiation, and 
granulomatous diseases can also affect the neuroendocrine components of the 
(HPA) axis.  
1.2 
Background and Rationale  
Central adrenal insufficiency can be challenging to diagnose, as patients often 
present with nonspecific symptoms of weakness, malaise, and nausea. 
Furthermore, patients with partial adrenal insufficiency may be asymptomatic until 
they encounter major physiologic stress. Currently, CAI is diagnosed with basal 
testing and/or dynamic testing. Basal testing that reveals low morning cortisol and 
ACTH suggests CAI. If basal testing is equivocal, dynamic testing is typically 
completed with cosyntropin stimulation test. Cosyntropin stimulation testing can 
diagnose or rule out primary adrenal insufficiency, but can also be equivocal in CAI. 
The gold standard for diagnosing CAI is dynamic testing with the insulin tolerance 
test (ITT); metyrapone testing is also used. ITT protocol requires administration of 

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insulin to induce hypoglycemia, followed by serial measurements of cortisol and 
ACTH response. However, ITT is uncomfortable for patients and poses risks 
associated with hypoglycemia, such as precipitation of cardiac events or seizures. 
Metyrapone testing is challenging, because it requires measurement of 11-
deoxycortisol, and there is often cross-reactivity between 11-deoxycortisol with 
cortisol in commercial immunoassays.ii 
Secondary adrenal insufficiency is a rare diagnosis and data on mifepristone use as 
a diagnostic tool is unavailable in these patients. Therefore, the current study will 
test recruitment of this population as the primary endpoint. 
 
 
 

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1.3 
Hypothesis 
With regards to the primary endpoint we propose that we can reach a target 
average recruitment of one patient every 6 weeks for a time study duration of 36 
months.  
With regards to the secondary endpoint we propose the use of mifepristone as an 
alternative dynamic testing reagent for CAI. Mifepristone is a glucocorticoid and 
progesterone receptor antagonist. In normal participants, mifepristone would be 
expected to cause a rise in morning cortisol. In subjects with CAI, morning cortisol 
will remain low. This alternative test would avoid patient discomfort associated with 
hypoglycemia required with insulin tolerance testing, and avoid the need to measure 
surrogate parameters, such as 11-deoxycortisol required with metyrapone testing. 
 
1.4 
Previous Human Experience 
Mifepristone is a glucocorticoid and progesterone receptor antagonist. While it is 
well-known as an abortifacient agent, it is also used and FDA-approved for medical 
management of Cushing’s syndrome. Prior studies have demonstrated that 
administration of mifepristone causes a dose-dependent increase in morning ACTH 
and cortisol starting at a dose of 4.5mg/kg.iii Furthermore, the concurrent 
administration of mifepristone and evening dexamethasone 1mg resulted in normal 
morning ACTH and cortisol, indicating that mifepristone disinhibits HPA suppression 
by dexamethasone. Of note, these effects of mifepristone on ACTH and cortisol 
levels were only noted in hormone levels in the morning.  

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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
This study can be viewed as having two phases. The primary (first phase) objective 
of this pilot-feasibility study is to evaluate, whether recruitment of participants can 
be reached.  
The secondary (phase II) objective is analysis of cortisol response to mifepristone in 
participants without history of adrenal insufficiency compared to participants with 
confirmed or suspected adrenal insufficiency. The cortisol response with 
mifepristone administration will be compared with the maximal cortisol response of 
the insulin tolerance test to determine whether there is any correlation between the 
two values.  
Another objective of the study is to evaluate the effects of mifepristone on other 
steroid hormones and metabolites. The last objective is to determine whether there 
is a statistically large enough difference between the ACTH and cortisol response in 
healthy participants and those with adrenal insufficiency, to indicate that 
mifepristone could be used as an agent for diagnosis of central adrenal 
insufficiency.  

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2.2 
Endpoints 
2.2.1 
Primary Endpoint  
The primary endpoint of this pilot feasibility study is actual study participant 
recruitment. Reaching the target recruitment rate of one patient every 6 weeks over 
a 36-month period will be regarded as successful in reaching the primary endpoint.  
2.2.2 
Secondary Endpoint 
 
The secondary endpoint is the correlation between the peak cortisol measured in 
ITT (the gold standard) and the cortisol measured the day after mifepristone 
administration. We will assess whether there is a strong relationship between ITT 
peak cortisol and the cortisol measured after mifepristone administration. We 
hypothesize that the Pearson’s correlation coefficient (r) for this correlation will be > 
0.7. The results of the ITT will be regarded as the gold standard in the diagnosis of 
secondary adrenal insufficiency. As the true cut-off for diagnosis of adrenal 
insufficiency using post-mifepristone cortisol is unknown we will analyze the data 
using ROC c-statistics for different cut-offs. 
2.2.3 
Exploratory Endpoints 
 
Exploratory endpoints include the impact of mifepristone on ACTH and other steroid 
hormones and metabolites, such as but not limited to corticosterone, aldosterone, 
androstenedione, 11-deoxycortisol, 11-deoxycorticosterone, DHEAS, DHEA, 17-
hydroxyprotesterone, 17-hydroxypregnenolone. Analysis will be done by c-statistics 
in comparison the gold standard of ITT peak cortisol as well. 
 

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3 STUDY DESIGN  
This will be a single-center trial of mifepristone to evaluate the ACTH and cortisol 
response to mifepristone in participants without history of adrenal insufficiency and 
participants with confirmed or suspected adrenal insufficiency. All adult participants 
who have undergone ITT from 2012 to present, are scheduled to undergo ITT in the 
future, or are clinically suspected to have adrenal insufficiency, will be approached 
for this study. There will be at least a one-week interval between ITT and 
mifepristone testing.  
Subjects who meet inclusion criteria and agree to participation will undergo the 
study conducted over two days: baseline hormone labs will be obtained on the 
morning of day 1. A single dose of 600mg mifepristone is to be orally taken at 10PM 
on day 1. Participants will then return for repeat lab work on day 2. 
 
 
 
 

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4 SUBJECT SELECTION 
4.1 
Subject Recruitment 
The study population will include adult male and female patients (n = 20), who 
underwent ITT from 2012 to present, are scheduled to undergo ITT in the future, or 
are clinically suspected to have adrenal insufficiency. 
Eligible participants will be identified through a EMERSE and Data Direct search of 
individuals who have undergone ITT between 2012 and present, who have ITT 
ordered to be completed, or who have adrenal insufficiency listed as a clinical 
diagnosis. In addition, eligible participants will be recruited through physician 
referral and through review of clinic schedules listing individuals scheduled for ITT. 
 
 
Patients will be called and offered participation by the study staff. 
4.1.1 
Inclusion Criteria 
Adult (ages ≥ 18 years of age) male and female subjects who: 
1. Completed ITT at University of Michigan from 2012 to present. 
OR  
2. Are scheduled to complete ITT. 
OR 
3. Are clinically suspected to have adrenal insufficiency but have not undergone 
ITT. 
4.1.2 
Exclusion Criteria 
1. Female patients who are of child-bearing potential (defined as a sexually mature 
woman who has not undergone hysterectomy, bilateral oophorectomy bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 12 weeks prior to 
screening, or who has not been naturally postmenopausal for at least 24 
consecutive months prior to study enrollment) and not using non‐hormonal 
contraception.  

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2. Female patients not willing to use non-hormonal contraception for one month 
following treatment. 
3. Women who are breast feeding. 
4. Female patients who have a positive pregnancy test.   
5. Female patients with unexplained vaginal bleeding or history of endometrial 
hyperplasia with atypia or carcinoma.   
6. Patients with an existing diagnosis of adrenal insufficiency who are on any 
glucocorticoid replacement other than oral hydrocortisone or prednisone.  
7. Patients with hypokalemia < 3.5 mEq/L on lab work completed on Day 1 or 
obtained within 3 months prior to Day 1.  
8. Patients with AST or ALT greater than 3 times the upper limit of normal on lab 
work completed on Day 1 or obtained within 3 months prior to Day 1.  
9. Hypertensive patients with uncontrolled blood pressure defined as SBP > 180 
and/or DBP > 100. 
10. Patients on medications that are CYP3A substrates with narrow therapeutic 
ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, and tacrolimus. 
11. Patients on medications that are strong CYP3A inhibitors (such as itraconazole, 
nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, 
fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, mibefradil, 
posaconazole, saquinavir, telaprevir, telithromycin, and voriconazole) or 
inducers (such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, 
carbamazepine, St. John’s wort).  
12. Patients taking other medications metabolized by CYP3A, such as simvastatin, 
lovastatin. 
13. Patients who are not euthyroid as judged by the investigator.  
14. Patients with history of hypersensitivity to mifepristone or the tablet components  
15. Patients who have a history of QT prolongation and patients with any recent 
abnormal ECG. 
 
 

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5 STUDY TREATMENTS 
 
5.1 
Allocation to Treatment 
All subjects will be in the treatment group. 
5.2 
Breaking the Blind 
Not applicable. 
5.3 
Drug Supplies-Mifepristone 
 
• 
Other names for the drug: KORLYM®, C1073, RU486 
 
• Description: 300 mg tablets are light yellow to yellow, oval-shaped, film-coated 
tablets debossed with “Corcept” on one side and “300” on the other. Each bottle 
contains 28 tablets. 
 
• 
Mode of action: Mifepristone is a selective antagonist of the progesterone 
receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher 
doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the 
GR-I (MR, mineralocorticoid) receptor. 
 
• Pharmacokinetics: 
Absorption 
Following oral administration pf mifepristone to healthy volunteers, time to 
peak plasma concentrations of mifepristone occurred between 1 and 2 hours 
following single dose, and between 1 and 4 hours following multiple doses of 
600 mg. The mean plasma concentrations of the three active metabolites of 
mifepristone peak between 2 and 8 hours after multiple doses of 600 mg/day, 
and the combined concentrations of the metabolites exceed that of the parent 
mifepristone. Exposure to mifepristone is substantially less than dose 
proportional. Time to steady state is within 2 weeks, and the mean (SD) half-
life of the parent mifepristone was 85 (61) hours following multiple doses of 
600 mg/day of mifepristone. Studies evaluating the effects of food on the 
pharmacokinetics of mifepristone demonstrate a significant increase in 
plasma levels of mifepristone when dosed with food.  
 
Distribution 
Mifepristone is highly bound to alpha-1-acid glycoprotein (AAG) and 
approaches saturation at doses of 100 mg (2.5 μM) or more. Mifepristone 
and its metabolites also bind to albumin and are distributed to other tissues, 
including the central nervous system (CNS).  

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Metabolism 
Cytochrome P450 3A4 (CYP3A4) has been shown to be involved in 
mifepristone metabolism in human liver microsomes. Two of the known 
active metabolites are the product of demethylation (one monodemethylated 
and one di-demethylated), while a third active metabolite results from 
hydroxylation (monohydroxylated). 
 
Elimination and Excretion 
Excretion is primarily (approximately 90%) via the fecal route. Excretion in the 
urine accounts for less than 10%. 
• 
Side effects:  The most common adverse reactions reported in patients with 
Cushing's syndrome (≥ 20%) include: nausea, fatigue, headache, decreased 
blood potassium, arthralgia, vomiting, peripheral edema, hypertension, 
dizziness, decreased appetite, and endometrial hypertrophy. Refer to the current 
FDA-approved label of Korlym® for the most comprehensive and up to date 
information on side effects. However, these adverse reactions are observed in 
patients with Cushing syndrome and are likely due to a contribution by steroid 
withdrawal syndrome.  
 
• 
Drug Interactions:  
CYP3A 
• 
The use of mifepristone with drugs whose metabolism is primarily mediated 
by CYP3A (substrates) is likely to result in increased plasma concentrations 
of the drug. Mifepristone is contraindicated in patients taking simvastatin, 
lovastatin, and CYP3A substrates with narrow therapeutic ranges. 
Instructions on handling drugs with high or low first pass metabolism in which 
CYP3A is the primary or the minor route of metabolism are provided in the 
current FDA-approved label of Korlym®. 
• Medications that inhibit CYP3A could increase plasma mifepristone 
concentrations and dose reduction of mifepristone may be required.  
• Mifepristone has not been studied with CYP3A inducers. CYP3A inducers 
could decease the plasma concentration of mifepristone and therefore, co-
administration should be avoided. 
Cytochrome P450 (CYP) 2C8/2C9 
• Co-administration of mifepristone with drugs primarily metabolized by 
CYP2C8/2C9 (substrates) would be expected to result in an increased 
plasma concentration of that drug. For example, mifepristone significantly 
increased exposure of the CYP2C8/2C9 substrate fluvastatin. Substrates of 
these enzymes (e.g., non-steroidal anti-inflammatory drugs, warfarin, 
repaglinide) should be used at the smallest recommended doses and 

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monitored closely for adverse effects.  
 
CYP2B6 substrates 
• No study has been conducted on the effects of mifepristone on CYP2B6 
substrates. Mifepristone is a CYP2B6 inhibitor and may cause significant 
increase in exposure to drugs that are metabolized by CYP2B6. Caution 
should be exercised when mifepristone is used concomitantly with CYP2B6 
substrates such as bupropion.  
 
Hormonal Contraceptives 
• Mifepristone is a progesterone-receptor antagonist and will interfere with the 
effectiveness of hormonal contraceptives. Therefore, non-hormonal 
contraceptive methods should be used. 
 
Refer to the current FDA-approved label of Korlym® for the most comprehensive 
and up to date information on drug-drug interactions with mifepristone. 
 
• 
Storage and stability: Mifepristone tablets should be stored at controlled room 
temperature, 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F). [See 
USP Controlled Room Temperature]. Mifepristone bottles must be stored in a 
secure, limited access area.   
 
• 
Preparation and Dispensing: Count the appropriate number of tablets into a 
prescription bottle and label with a patient-specific label. 
 
• 
Administration: Mifepristone tablets should not be crushed, split, or chewed. 
  
• 
Availability: The investigational drug will be provided by Corcept from the same 
supply as the commercial drug. Under no circumstance will the study 
medication, mifepristone, be used other than as directed by the protocol.  
 
• Return and Retention of Study Drug: Drug that expires during the study or 
remains at the site at the end of the study should be discarded on site according 
to the institutional standard operating procedure for drug destruction. The drug 
disposition should be documented in the drug accountability logs. The logs 
including the quantity and lot number of the destroyed drug should be provided 
to the sponsor. 
 
• 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of 
the investigational drug, mifepristone. The drug accountability records will 
capture drug receipt, drug dispensing, and final disposition.   
 

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5.4 
Concomitant medications 
Patients on medications listed in the exclusion criteria will not be included in the 
study.  
6 STUDY PROCEDURES- SEE THE SCHEDULE OF ACTIVITIES 
6.1 
Screening Visit   
Potential subjects will be contacted over the phone to review their past medical 
history and current medications. If the potential participant is a woman of 
childbearing potential, she will be asked to take an at-home urine pregnancy test or 
come in for a urine or serum pregnancy test one week prior to visit 1. If they do not 
meet any pre-screening exclusion criteria, they will present for Day 1 of the study 
and complete screening labs on this day. 
6.2 
Treatment Study Period 
6.2.1 
Visit 1 (Day 1)  
Subject will be presented the consent document prior to any procedures on this day. 
Between 7AM and 9AM, baseline labs, including morning cortisol, ACTH, and other 
steroid hormones and metabolites (5ml serum, 5ml EDTA) and a serum pregnancy 
test will be obtained. A comprehensive metabolic panel and complete blood count 
will be obtained if not already performed in the prior 3 months. Patients will be 
provided a single dose of 600mg mifepristone to be administered orally, and 
subjects will be instructed to take the drug between 10PM and 11PM on Day 1. 
If the participant is scheduled for an ITT as part of their medical care and is 
consented for this study prior to completing ITT, the study team will attempt to 
obtain left over blood samples for measurement of baseline labs relevant for 

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mifepristone testing, if the serum is drawn before 10AM, the lab draw that is part of 
Day 1 of the study could be omitted in this scenario.  
6.2.2 
Follow-up  
On Day 2, subjects will return to the clinic. it will be confirmed with the participants 
that they took mifepristone at the recommended time the previous night. We will 
obtain vital signs. Between 7AM and 9AM, repeat complete blood count (CBC), 
serum chemistry and hormone labs will be obtained. Adverse events will be 
collected.  
On Day 7 and Day 30, participants will be contacted by phone to assess for any 
adverse events that occurred since Day 1. 
6.2.3 
Subjects with history of adrenal insufficiency 
Subjects with confirmed history of adrenal insufficiency (AI) on glucocorticoid 
replacement at baseline will be instructed on the following protocol for glucocorticoid 
dosing during testing. All components of the study protocol are otherwise the same 
as above.  
- 
Day 0: Take the morning dose of glucocorticoid and hold the afternoon dose. 
- 
Day 1: Hold the morning dose until labs are drawn, then take the morning dose. 
Hold the afternoon dose. 
- 
Day 2: Hold the morning dose until labs are drawn, then take the morning dose 
and resume baseline dosing schedule. 
• Withholding afternoon doses of glucocorticoids for testing is routinely done in 
clinical practice and considered safe. Participants with diagnosed AI will be 
provided with a prescription for 4 mg of dexamethasone.  Participants will be 

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provided with two 24-hour phone numbers to call if/when they experience any 
side effects. . Participants will be instructed to take 4mg of dexamethasone in 
case they experience significant signs of acute adrenal insufficiency [increasing 
nausea, lethargy, diarrhea, fever]. Participants are encouraged to contact one of 
the 24-hour phone numbers prior to taking the dexamethasone and are advised 
to call the number after taking the dexamethasone. As participants are 
scheduled for a blood draw the next morning they will be clinically assessed for 
adrenal insufficiency in case overnight concerns occur and further management 
will depend on this clinical evaluation. On day 2, participants with adrenal 
insufficiency will resume their usual dose of hydrocortisone replacement therapy 
and occurrence of adrenal insufficiency will become less likely.  However, 
participants will remain advised to keep the dexamethasone emergency dosing 
and to contact the study team in case of any symptoms and signs of adrenal 
insufficiency

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Table 1.  
Schedule of Activities 
 
Protocol Activity 
 
Screening 
Phone Call 
 
Screening / Day 1a 
Day 2 
Day 7 
 (+/- 3 days) 
Phone Call 
Day 30 Phone Call 
(+/- 3 days)  
 
 
 
 
 
 
Visit # / Phone call 
1 
1 
2 
3 
4 
Informed Consent  
 
X 
 
 
 
Medical History 
X 
X 
 
 
 
Vitals Signs b 
 
X 
X 
 
 
Serum Chemistry c 
 
X 
X 
 
 
Complete Blood Count 
 
X 
X 
 
 
Pregnancy Test d 
X 
X 
 
 
 
Hormone Labs e 
 
X 
X 
 
 
Treatment with study 
agent (10 pm) 
 
X 
 
 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
 
 
a. There will be at least a one-week interval between ITT and mifepristone testing.   
b. Vital signs: height (Day 1 only), weight (Day 1 only), temperature, heart rate, blood pressure. 
c. Serum chemistry: comprehensive metabolic panel. Day 1 labs will be omitted if completed and documented in the patient 
electronic medical record within the prior 3 months. Day 2 labs will be obtained in all cases. 
d. Urine pregnancy test at home 1 week before scheduled visit or come in to have urine or serum pregnancy test. Day 1 
visit will include a Serum pregnancy test (women of childbearing potential) 
e. Hormone labs: ACTH, cortisol and steroid profile (including but not limited to corticosterone, aldosterone, 
androstenedione, 11-deoxycortisol, 11-deoxycorticosterone, DHEAS, DHEA, 17-hydroxyprotesterone, 17-
hydroxypregnenolone). These must be drawn between 7 and 9 AM. 

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7 ASSESSMENTS  
 
7.1 
Primary Endpoint Assessments 
The primary endpoint of this pilot feasibility study is the rate of actual study 
participant recruitment. Reaching the target recruitment rate of one patient per 6 
weeks over a 36-month period will be regarded as successfully in reaching the 
primary endpoint. 
7.2 
Secondary Assessments  
The secondary endpoint is the correlation between cortisol measured after 
mifepristone administration and the peak cortisol measured in ITT. The results of 
the ITT will be regarded as the gold standard in diagnosis of diagnosis of secondary 
adrenal insufficiency. We expect that this correlation, as measured with the Pearson 
correlation coefficient (r) will be > 0.7. As the true cut-off for diagnosis of adrenal 
insufficiency using post-mifepristone cortisol is unknown, we will analyze the data 
using ROC c-statistics for different cut-offs. 
7.3 
Exploratory Assessments  
Exploratory endpoints include the impact of mifepristone on ACTH and other steroid 
hormones and metabolites, such as but not limited to corticosterone, aldosterone, 
androstenedione, 11-deoxycortisol, 11-deoxycorticosterone, DHEAS, DHEA, 17-
hydroxyprotesterone, 17-hydroxypregnenolone. Analyses will be completed with c-
statistics as well. 
 

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8 ADVERSE EVENT REPORTING 
 
8.1 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject participating in 
an investigational study or protocol regardless of causality assessment.  An adverse 
event can be an unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, syndrome or disease associated with or occurring during the use of 
an investigational product whether or not considered related to the investigational 
product. 
These events may be: 
a. Definitely related: clearly associated with study drug/treatment 
b. Probably related:  likely associated with study drug/treatment 
c. Possibly related:  may be associated with study drug or other treatment 
d. Unlikely to be related, or 
e. Definitely not related to the study drug/treatment 
For reporting purposes, an AE should be regarded as definitely or probably related to 
the regimen if the investigator believes that at least one of following criteria are met: 
a. There is a clinically plausible time sequence between onset of the AE and the 
administration of the study drug or treatment. 
b. There is a biologically plausible mechanism for the study drug or treatment causing 
or contributing to the AE. 
c. The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures.  
d. A potential alternative cause does not exist. 

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Serious Adverse Events (SAE):  An adverse drug experience occurring at any dose 
that results in any of the following outcomes: 
a. 
Death 
b. 
A life-threatening adverse drug experience 
c. 
Inpatient hospitalization or prolongation of existing hospitalization 
d. 
A persistent or significant disability &/or incapacity 
e. 
A congenital anomaly or birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. A serious adverse experience includes any experience that is fatal or 
immediately life threatening, results in a persistent or significant disability/incapacity, 
requires or prolongs in-patient hospitalization, or is a congenital anomaly, cancer, or 
overdose. 
Other important medical events that may not result in death, not be life-threatening, or 
not require hospitalization may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the 
subject/patient and may require medical or surgical intervention to prevent one of the 
outcomes listed previously. 
 

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Expected adverse events are those adverse events that are listed in the protocol, the 
drug label, the Investigator’s Brochure (version 18, June 2017), published literature, or 
in the study informed consent document. 
Unexpected adverse events are those that: 
a. are not described in the Investigator's Brochure or drug label as far as drug is 
concerned. 
b. are not anticipated in the study informed consent.  This includes adverse events for 
which the specificity or severity is not consistent with the description in the informed 
consent. 
Unanticipated problem: Per FDA Procedural Guidance for Clinical Investigators, 
Sponsors, and IRBs (January 2009), A serious problem that has implications for the 
conduct of the study (requiring a significant and usually safety-related, change in the 
protocol such as revising inclusion/exclusion criteria or including a new monitoring 
requirement, informed consent or investigator’s brochure). 
Unanticipated problem Reporting: Per 21 CFR 312.66, 312.53 (c)(1)(vii), and 
56.108(b)(1), should an Unanticipated problem occur during the investigation, the 
investigator will promptly report all unanticipated problems involving risks to human 
subjects or others to IRBMED /FDA. 
The severity or grade of an adverse event may be measured using the following 
definitions: 
Mild:  Noticeable to the subject, but does not interfere with subject’s expected daily 
activities, usually does not require additional therapy or intervention, dose reduction, or 
discontinuation of the study. 

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Moderate:  Interferes with the subject’s expected daily activities, may require some 
additional therapy or intervention but does not require discontinuation of the study. 
Severe: Extremely limits the subject’s daily activities and may require discontinuation 
of study therapy, and/or additional treatment or intervention to resolve. 
8.2 
Event reporting:  
The study will comply with the IRB & FDA reporting requirements and guidelines. 
8.2.1 
Serious Adverse Event Reporting Guidelines 
The Principal Investigator must be notified within ONE business day of study team’s 
knowledge of any event meeting the criteria and definition of a serious adverse event, 
regardless of attribution, occurring during the study or within 30 days of the last 
administration of the study related intervention. 
The investigator must report all events meeting the criteria and definition of a serious 
adverse event as per the local IRB reporting requirements. Participants will be given 
contact information for study staff should they need to report any adverse events.  
The Sponsor-Investigator will coordinate with the Michigan Institute for Clinical and 
Health Research (MICHR) IND/IDE Assistance Program (MIAP) office for the 
reporting of any and all IND safety reports to the FDA as per the requirements 
outlined in 21 CFR312.32 which include all SAEs that are both unexpected and 
related to the intervention/treatment. 
 

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8.2.2 
Routine Reporting 
Lab results that are out of normal range but not clinically significant will not be reported. 
All other adverse events, such as those that are expected, or are unlikely or definitely 
not related to the study participation, are to be reported annually as part of regular data. 
9 DATA ANALYSIS/STATISTICAL METHODS 
9.1 
Sample Size Determination 
This is a pilot-feasibility study with the primary endpoint of enrollment per month 
over a 36-month period. This study time frame was chosen due to the lack of any 
prior data regarding feasibility. Data required form this study will inform the planning 
of a post-pilot study.  
 
9.2 
Data Analysis 
9.2.1 
Analysis Populations 
As the primary endpoint recruitment will be analyzed as a primary endpoint. The 
cortisol response with mifepristone administration will be compared with the 
maximal ITT cortisol level in all patients as a secondary endpoint. In addition, the 
hormone levels of participants with normal ITT will be compared to those with 
confirmed diagnosis of central adrenal insufficiency. Data from this study will inform 
planning of a larger post-pilot study. 

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9.2.2 
Analysis of Primary Endpoint 
The primary endpoint of this pilot feasibility study is actual study participant 
recruitment. Reaching the target recruitment of one participant every 6 weeks over 
a 36-month period (target n=26) will be regarded successful in reaching the primary 
endpoint. We estimate an enrollment of 90% of patients in this study. This is in 
accordance with our prior experience in patients with rare diseases, who are often 
motivated regarding study participation. We estimate a total of 85% of patients with 
complete data as we only anticipate minimal study drop out due to side effects of 
the drug or non-analyzable specimens. Study recruitment will be plotted over time 
and actual and target recruitment will be visually compared. We will regard a total of 
22 patients as a target in meeting the primary endpoint.   
 
9.2.3 
Analysis of Secondary Endpoints 
The secondary data point is day 2 cortisol and ACTH response to mifepristone 
administration. The day 2 cortisol level will be compared to the maximal ITT cortisol 
level to determine if and to what degree there is a correlation between the two 
measurements. In addition, a receiver operating characteristic (ROC) curve will be 
created with the day 2 cortisol level as the variable, and the ITT result as the “gold 
standard” test for adrenal insufficiency, to analyze the performance of cortisol as a 
diagnostic test. The cortisol and ACTH values in participants with normal ITT will be 
compared to those with confirmed diagnosis of central adrenal insufficiency, using a 

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t-test to determine whether there is statistically significant difference between the 
two populations.  
9.2.4 
Analysis of Secondary Endpoints 
The secondary end points are levels of ACTH, other (than cortisol) steroid 
hormones and metabolites. These hormone levels will also be analyzed with t-tests 
to determine whether there is a statistically significant difference between 
participants with normal ITT and those with confirmed diagnosis of central adrenal 
insufficiency.  
 

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10 MONITORING 
To assure adequate protection of the rights of human subjects, per 21 CFR 
§312.50, 312.53, this study will be monitored by the University of Michigan 
Institute for Clinical and Health Research (MICHR).  Routine monitoring will be 
scheduled at appropriate intervals, with more frequent visits occurring at the 
beginning of the study. An initiation visit will take place, followed by routine 
monitoring visits. Additional visits can be scheduled at the request of the Project 
Manager. 
The established monitoring plan will ensure the quality and integrity of the data 
through pre- investigation visits and periodic site visits to verify adherence to the 
protocol, completeness and accuracy of study data and samples collected, 
proper storage, dispensing and inventory of study medication, and compliance 
with regulations. 
11 DATA HANDLING AND RECORD KEEPING 
11.1 CRFs / Electronic Data Record 
Data will be protected by several different measures throughout the life of the study. 
Paper documents and records will be stored in a secured location with restricted 
access to authorized personnel only.  Electronic study documents and data will be 
kept in a password protected environment, whereby access rights will be terminated 
at the request of the PI when study members leave the project. 

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11.2 Record Retention 
Per 21 CRF §312.62, study records will be retained for 2 years after the 
investigation is discontinued. 
 

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12 ETHICS 
12.1 IRB/FDA 
Prior to study commencement, an Investigator Initiated Investigational New Drug 
(IND) will be submitted to the Food and Drug Administration (FDA), for review and 
approval. Prior to study commencement, an Investigator Initiated Investigational 
New Drug (IND) will be submitted to the Food and Drug Administration (FDA), for 
review and approval. The study will also be reviewed and approved by the 
Institutional Review Board (IRBMED, University of Michigan, Ann Arbor, MI). 
12.2 Institutional Review Board (IRB) 
Before implementing this study, the protocol, the proposed informed consent form 
and other information to be provided to subjects, must be reviewed by a properly 
constituted Institutional Review Board (IRB). Any amendments to the protocol must 
be reviewed and approved by IRBMED. 
12.3 Subject Information and Consent 
The study team member will explain to each subject (or legally authorized 
representative) the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved and any discomfort it 
may entail.  Each subject will be informed that participation in the study is voluntary 
and that he/she may withdraw from the study at any time and that withdrawal of 
consent will not affect his/her subsequent medical treatment or relationship with the 
treating physician. 

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This informed consent will be given by means of a standard written statement, 
written in non-technical language. The subject should read and consider the 
statement before signing and dating it, and should be given a copy of the signed 
document. If the subject cannot read or sign the documents, oral presentation may 
be made or signature given by the subject’s legally appointed representative, if 
witnessed by a person not involved in the study, mentioning that the patient could 
not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and will be 
submitted for IRB approval. 
12.4 STUDY DISCONTINUATION CRITERIA 
12.4.1 
Stopping Rules for Safety reasons 
There will be no Data Safety Monitoring Board as this is a single site study. 
However, we will continuously review SAE. If a study related SAE occurs in 3 of 6 
patients or in >50% of patients at any time, the study will be terminated. 
12.4.2 
Rules for Discontinuation of a Subject 
In the event a patient drops out of the study or is discontinued due to protocol 
violations, all attempts will be made to exit the patient in accordance with the 
protocol requirements. 
 

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13 REFERENCES 
 
 
 
 
i Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014 
Jun 21;383(9935):2152-67. 
ii Monaghan PJ, Owen LJ, Trainer PJ, Brabant G, Keevil BG, Darby D. Comparison 
of serum cortisol measurement by immunoassay and liquid chromatography-
tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor 
metyrapone. Annals of clinical biochemistry. 2011 Sep;48(Pt 5):441-6. 
iii Gaillard RC, Riondel A, Muller AF, Herrmann W, Baulieu EE. RU 486: a steroid 
with antiglucocorticosteroid activity that only disinhibits the human pituitary-adrenal 
system at a specific time of day. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3879-
82.