A Study of the Efficacy and Safety of CORLUX in the Treatment of Endogenous Cushing's Syndrome

Cushing's Syndrome Clinical Trial

— SEISMIC  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00569582
• Other study ID #: C-1073-400
• Status: Completed
• Phase: Phase 3
• First received: December 5, 2007
• Last updated: August 12, 2013
• Start date: December 2007

Study information

• Verified date: August 2013
• Source: Corcept Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cushing Syndrome
• Cushing's Syndrome
• Syndrome

Intervention

Drug:
• mifepristone
Patients take mifepristone by mouth once a day. The dose is increased during scheduled timepoints during the study or until symptoms improve or the highest dosage allowed is reached. Dose escalation will be based upon weight. During clinic visits, blood pressure, glucose tolerance and blood chemistries are measured and EKG and urinalysis will be performed.

Locations

Country	Name	City	State
United States	University of New Mexico HSC	Albuquerque	New Mexico
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	University of Alabama at Birmingham School of Medicine	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern University Feinberg Medical; Division of Endocrinology, Metabolism & Molecular Medicine	Chicago	Illinois
United States	The University of Chicago	Chicago	Illinois
United States	Cleveland Clinic Foundation; Dept of Endocrinology, Diabetes & Metabolism	Cleveland	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	AMCR Institute Inc.	Escondido	California
United States	The Center for Diabetes and Endocrine Care	Hollywood	Florida
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Endocrinology Center at North Hills, Froedtert and Medical College of Wisconsin	Menomonee Falls	Wisconsin
United States	Oklahoma University Health Science Center	Oklahoma City	Oklahoma
United States	Oregon Health Sciences University	Portland	Oregon
United States	Diabetes and Glandular Disease Clinic	San Antonio	Texas
United States	Stanford University Medical Center	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Corcept Therapeutics

Country where clinical trial is conducted

United States, 

References & Publications (8)

Agarwai MK. The antiglucocorticoid action of mifepristone. Pharmacol Ther. 1996;70(3):183-213. Review. — View 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. — View 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 — View Citation

Johanssen S, Allolio B. Mifepristone (RU 486) in Cushing's syndrome. Eur J Endocrinol. 2007 Nov;157(5):561-9. Review. — View Citation

Miller JW, Crapo L. The medical treatment of Cushing's syndrome. Endocr Rev. 1993 Aug;14(4):443-58. Review. — View Citation

Morris D, Grossman A. The medical management of Cushing's syndrome. Ann N Y Acad Sci. 2002 Sep;970:119-33. Review. — View 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. — View Citation

Sartor O, Cutler GB Jr. Mifepristone: treatment of Cushing's syndrome. Clin Obstet Gynecol. 1996 Jun;39(2):506-10. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Improvement in Diabetes and/or Glucose Intolerance.	Responder is defined as subject with a decrease greater than or equal to 25% in area under the curve for glucose on 2-hour oral glucose test from baseline to week 24 or last visit, for Cushing's patients with type-2 diabetes mellitus/impaired glucose tolerance.	Baseline to Week 24	No
Primary	Decrease in Diastolic Blood Pressure.	Responder is defined as subject with a decrease greater than or equal to 5mm Hg in diastolic blood pressure from baseline to week 24 or last visit.	Baseline to Week 24	No

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