Clinical trial NCT00569582: A Study of the Efficacy and Safety of CORLUX in the Treatment of Endogenous Cushing's Syndrome
Official title: An Open-label Study of the Efficacy and Safety of CORLUX (Mifepristone) in the Treatment of the Signs and Symptoms of Endogenous Cushing's Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cushing's Syndrome
Keywords: Cushing's Disease
Cushing's Syndrome
Cushings
Pituitary
ACTH
Adrenocorticotropic hormone
Ectopic
Adrenal adenoma
Adrenal carcinoma
Adrenal autonomy
Cortisol
Hypercortisolemia
Cushingoid
Moon facies
Dorsocervical fat
Plethora
Hirsutism
Violaceous striae
Hormone
Contraceptive
Endocrine
Cushing Syndrome
Ectopic ACTH Secretion
Lead sponsor: Corcept Therapeutics
Sponsor class: INDUSTRY
First posted: 2007-12-07
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Patients will receive Corlux (mifepristone) daily for up to 24 weeks. Assessments of the signs and symptoms of Cushing's syndrome will be obtained.

Detailed description: Cushing's syndrome is a relatively rare disorder caused by prolonged exposure to high levels of the glucocorticoid hormone cortisol. Cushing's syndrome may result from elevated endogenous or exogenous sources of cortisol. Endogenous Cushing's syndrome resulting from cortisol overproduction by the adrenal glands is the subject of this protocol. Patients with exogenous Cushing's syndrome, which develops as a side effect of chronic administration of high doses of glucocorticoids, are not eligible for enrollment in this study.

This will evaluate the safety and efficacy of mifepristone for treatment of the signs and symptoms of hypercortisolemia in patients with endogenous Cushing's syndrome from ACTH-dependent or adrenal disorders.

The study will enroll subjects for whom the investigator has determined that medical treatment of endogenous hypercortisolemia is needed. Medical treatment may be intended to treat the effects of persistent or recurrent hypercortisolemia after surgery and/or radiation for Cushing's syndrome, to bridge the period of time for radiation to become effective, or when surgery is not feasible.

Eligibility criteria: Inclusion Criteria:

Individuals eligible for enrollment into this study are adult male and non-pregnant female adult patients who:

* Are at least 18 years of age
* Have a confirmed diagnosis of endogenous hypercortisolemia caused by ACTH dependent or ACTH independent etiologies, including

  1. Cushing's Disease (that has recurred after primary pituitary surgery, or has failed pituitary surgery, or has been treated with radiation therapy to the pituitary, or is not treatable with surgery, or exists in patients who are not candidates for surgery, and is confirmed by documentation of ACTH immuno-reactivity on a pathological evaluation of pituitary tissue from a previous surgical specimen or IPSS with a central-to-peripheral gradient (ratio) of \>2 before or \>3 after CRH administration).
  2. Ectopic ACTH
  3. Ectopic CRF secretion
  4. Adrenal adenoma
  5. Adrenal carcinoma
  6. Adrenal autonomy
* Require medical treatment of hypercortisolemia
* Have diabetes mellitus type 2 or glucose intolerance AND/OR have hypertension \*Note: To be eligible for inclusion subjects must have documented evidence of persistent endogenous hypercortisolemia

Exclusion Criteria:

Individuals not eligible to be enrolled into the study are those who:

* Have de novo Cushing's disease and are surgical candidates for pituitary surgery.
* Have an acute or unstable medical problem, which could be aggravated by mifepristone treatment.
* Taking medications within 14 days of the baseline visit (Day 1) that a) have a large first pass metabolism largely mediated by CYP3A4 and a narrow therapeutic margin and/or b) are strong CYP3A4 inhibitors.
* Female patients of reproductive potential, who are pregnant or who are unable or unwilling to use medically acceptable, non-hormonal methods of contraception during the study.
* Have received investigational treatment (drug, biological agent or device) within 30 days of Screening
* Have a history of an allergic reaction or intolerance to CORLUX (mifepristone)
* Have a non-endogenous source of hypercortisolemia such as factious hypercortisolemia (exogenous source of glucocorticoid, iatrogenic Cushing's syndrome), factious or therapeutic use of ACTH
* Have Pseudo-Cushing's syndrome.
* Receive PPARgamma agonist drugs (e.g. pioglitazone, rosiglitazone) within 4 months of Baseline (Day 1).
* Postmenopausal women with an intact uterus who have experienced unexplained vaginal bleeding within 12 months of Screening are excluded.
* Have renal failure as defined by a serum creatinine of ≥2.2 mg/dL.

Primary outcomes:
measure: Improvement in Diabetes and/or Glucose Intolerance.
timeFrame: Baseline to Week 24
measure: Decrease in Diastolic Blood Pressure.
timeFrame: Baseline to Week 24
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine
state: Alabama
city: Escondido
country: United States
facility: AMCR Institute Inc.
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Hollywood
country: United States
facility: The Center for Diabetes and Endocrine Care
state: Florida
city: Chicago
country: United States
facility: Northwestern University Feinberg Medical; Division of Endocrinology, Metabolism & Molecular Medicine
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Albuquerque
country: United States
facility: University of New Mexico HSC
state: New Mexico
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation; Dept of Endocrinology, Diabetes & Metabolism
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Health Science Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: San Antonio
country: United States
facility: Diabetes and Glandular Disease Clinic
state: Texas
city: Menomonee Falls
country: United States
facility: Endocrinology Center at North Hills, Froedtert and Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Corcept Therapeutics
name: Coleman Gross
role: STUDY_DIRECTOR
References:
citation: Sartor O, Cutler GB Jr. Mifepristone: treatment of Cushing's syndrome. Clin Obstet Gynecol. 1996 Jun;39(2):506-10. doi: 10.1097/00003081-199606000-00024.
citation: Johanssen S, Allolio B. Mifepristone (RU 486) in Cushing's syndrome. Eur J Endocrinol. 2007 Nov;157(5):561-9. doi: 10.1530/EJE-07-0458.
citation: Morris D, Grossman A. The medical management of Cushing's syndrome. Ann N Y Acad Sci. 2002 Sep;970:119-33. doi: 10.1111/j.1749-6632.2002.tb04418.x.
citation: Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR, Feldman D. Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486). J Clin Endocrinol Metab. 2001 Aug;86(8):3568-73. doi: 10.1210/jcem.86.8.7740.
citation: Agarwai MK. The antiglucocorticoid action of mifepristone. Pharmacol Ther. 1996;70(3):183-213. doi: 10.1016/0163-7258(96)00016-2.
citation: Miller JW, Crapo L. The medical treatment of Cushing's syndrome. Endocr Rev. 1993 Aug;14(4):443-58. doi: 10.1210/edrv-14-4-443. No abstract available.
citation: Nieman LK, Chrousos GP, Kellner C, Spitz IM, Nisula BC, Cutler GB, Merriam GR, Bardin CW, Loriaux DL. Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486. J Clin Endocrinol Metab. 1985 Sep;61(3):536-40. doi: 10.1210/jcem-61-3-536.
citation: Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C; SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012 Jun;97(6):2039-49. doi: 10.1210/jc.2011-3350. Epub 2012 Mar 30.
citation: Fein HG, Vaughan TB 3rd, Kushner H, Cram D, Nguyen D. Sustained weight loss in patients treated with mifepristone for Cushing's syndrome: a follow-up analysis of the SEISMIC study and long-term extension. BMC Endocr Disord. 2015 Oct 27;15:63. doi: 10.1186/s12902-015-0059-5.
citation: Fleseriu M, Findling JW, Koch CA, Schlaffer SM, Buchfelder M, Gross C. Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. J Clin Endocrinol Metab. 2014 Oct;99(10):3718-27. doi: 10.1210/jc.2014-1843. Epub 2014 Jul 11.
citation: Wallia A, Colleran K, Purnell JQ, Gross C, Molitch ME. Improvement in insulin sensitivity during mifepristone treatment of Cushing syndrome: early and late effects. Diabetes Care. 2013 Sep;36(9):e147-8. doi: 10.2337/dc13-0246. No abstract available.