Mifepristone in Children With Refractory Cushing's Disease

The study is being done to examine the effects of a medication called mifepristone in
children with Cushing's disease. Since a child's body may absorb and use mifepristone in a
different way than adults, it is important to have information about the amount of
mifepristone to give children and what will happen to it. Mifepristone has been FDA approved
for use only in adults with Cushing's syndrome, and it is important to learn if mifepristone
improves the symptoms and signs of Cushing's disease in children. The study is limited to
children with Cushing's syndrome due to a pituitary tumor (Cushing's disease) and will not
enroll children with Cushing's syndrome due to other causes. The study will investigate how
children's bodies absorb and process mifepristone, how it works in children and what effect
it has on the use of sugar in the body, on the child's weight and on growth hormone. An
important part of the study is to evaluate the side effects of mifepristone in children.

Inclusion Criteria:

- Males and females 6-17 years at informed consent

- Active Cushing's disease as demonstrated by the following:

- 24 hour Urinary Free Cortisol greater than the upper limit of normal for age on two
urine collections during screening and

- midnight serum cortisol >4.4 mcg/dL (mean of two determinations on a single day at
2330 and 2400 during screening)

- Previous trans-sphenoidal surgery (TSS) for ACTH secreting pituitary tumor at least 3
months prior to screening

- Increased body weight defined by BMI Z-score of 1.5 or above

- Able to provide consent/assent

- Able to swallow study drug tablets (not crushed or split)

- Willing to use non-hormonal method of contraception in patients of reproductive
potential

- Primary health care provider in home location

Exclusion Criteria:

- Hypercortisolism not due to Cushing's disease.

- Type 1 diabetes mellitus

- HbA1c ≥9.5% at Screening

- Body weight <25 kg

- Use of certain medications that are CYP3A substrates with narrow therapeutic ranges,
such as simvastatin, lovastatin, cyclosporine, dihydroergotamine, ergotamine,
fentanyl, pimozide, quinidine, sirolimus, and tacrolimus during the 4 weeks prior to
starting study drug. Use of these medications is also prohibited until 2 weeks after
end of dosing.

- Use of certain 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 during the 2 weeks prior to
starting study drug. Use of these medications is also prohibited until 2 weeks after
end of dosing. Grapefruit and grapefruit juice, as well as grapefruit-related fruits
and their juice (e.g. Seville oranges, pomelos), are prohibited during this time
frame.

- Use of certain medications that are strong inducers of CYP3A such as rifampin,
rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, St. John's wort
during the 2 weeks prior to starting study drug. Use of these medications is also
prohibited until 2 weeks after end of dosing.

- Use of medications used to treat hypercortisolism from the duration indicated below
prior to Day 1. Use of the medications is also prohibited until after the end of
study 4 week follow up visit.

- steroidogenesis inhibitors such as ketoconazole, metyrapone: 4 weeks

- cabergoline, bromocriptine, somatostatin analogs such as octreotide, lanreotide,
pasireotide long acting formulations: 8 weeks (immediate release formulations: 2
weeks)

- mitotane: 8 weeks

- Use of systemic glucocorticoid medications beginning 1 month prior to screening or
anticipated use of these medications except for the treatment of adrenal
insufficiency. Use of glucocorticoid medications is prohibited during the study until
after the end of study 4 week study visit.

- Inflammatory, rheumatological, proliferative or other disorder(s) that would be
anticipated to worsen with glucocorticoid blockade (e.g. inflammatory bowel disease,
rheumatoid arthritis, psoriasis, etc.).

- Uncontrolled hypo- or hyperthyroidism.

- Uncorrected hypokalemia (<3.5 mEq/L). The screening period may be used to correct
hypokalemia prior to starting study drug. Use of potassium and/or mineralocorticoid
antagonists is permitted during the study.

- QTc ≥450 msec on Screening electrocardiogram

- Unexplained vaginal bleeding in females and/or any history of endometrial pathology.

- Positive pregnancy test in females.