Mifepristone in Children With Refractory Cushing's Disease

Study Overview
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Brief Summary
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Study objectives are to obtain safety, pharmacokinetic, and pharmacodynamic data on the effect of mifepristone on glucose metabolism, body weight and the growth-hormone-IGF in children with refractory Cushing's disease.

Detailed Description
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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.

Official Title
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An Open-label Study of the Safety, Pharmacokinetics and Pharmacodynamics of Mifepristone in Children With Refractory Cushing's Disease

Conditions
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Cushing's Disease

Intervention / Treatment
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* Drug: mifepristone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mifepristone<br>Daily doses of mifepristone over 84 days. | Drug: mifepristone<br>* tablets<br>* Other names: Korlym;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Patients who have received at least 1 dose of mifepristone will be included in the safety evaluations. | collected during the12 week study and 4 week follow-up period; up to 16 weeks total. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cushing's disease, Mifepristone, Cushing's syndrome, Pharmacokinetic-pharmacodynamic, Child/pediatric population, Safety-efficacy