Protocol Number: 07-CH-0008

Title:

Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion

Number:

07-CH-0008

Summary:

This study will evaluate whether the drug mifepristone can improve the symptoms of Cushing's syndrome in people with ectopic adrenal corticotrophin hormone (ACTH) secretion. Cushing's syndrome occurs when the adrenal glands produce too much cortisol, a hormone that helps to regulate the body's use of salt and food. Excessive cortisol is usually the result of too much ACTH, the hormone that causes the adrenal glands to make cortisol. The extra ACTH is made either by a tumor in the pituitary gland (called Cushing's disease) or by a tumor somewhere else (called ectopic ACTH secretion). Mifepristone blocks the action of cortisol in the body. The drug has been used safely to treat a few people with Cushing's syndrome and patients with certain kinds of cancer, gynecological diseases and psychiatric disorders.

People between 18 and 75 years of age with Cushing's syndrome caused by EXCESS ACTH secretion may be eligible for this study. Candidates are admitted to the hospital for evaluation to confirm Cushing's syndrome and to determine its cause. The evaluation includes blood and urine tests, imaging tests, dexamethasone and corticotropin-releasing hormone tests and inferior petrosal sinus sampling. Patients determined to have Cushing's syndrome due to ECTOPIC ACTH secretion undergo imaging studies (CT, MRI and a nuclear medicine scan) and begin mifepristone therapy.

Participants remain in the hospital for the following tests and procedures:

-Physical examination, electrocardiogram (EKG) and blood and urine tests

-Completion of medical questionnaires

-DEXA scan to determine bone mineral density and body composition

-Glucose tolerance test

-Urine pregnancy test and ultrasound to measure uterine lining thickness (for women)

Patients take mifepristone by mouth 3 times a day. The dose is increased every week or so until symptoms improve or the highest dosage allowed is reached. Patients may remain in the hospital for all or part of the dose-finding part of the study. During this period (usually 2 to 4 weeks), blood pressure, glucose tolerance and blood chemistries are measured and EKG and urinalysis done every 5 to 14 days. When the mifepristone dose is stable patients remain on that dose for at least 2 weeks and are then re-evaluated. Patients then return to the hospital for evaluations every 3 months. Those who do well on the drug may continue to take it for up to 12 months.

Sponsoring Institute:

National Institute of Child Health and Human Development (NICHD)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: Yes

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Subjects will be included if they have ALL of the three following criteria:

1. Hypercortisolism from Cushing's syndrome caused by ACTH ectopic secretion

AND

2. Glycemic disorder that is considered to be caused or worsened by the hypercortisolism

AND

3. At least one symptom attributable to the Cushing's syndrome.

EXCLUSION CRITERIA:

- Evidence for Cushing's disease as judged by positive inferior petrosal sinus sampling or a lesion on pituitary MRI with positive CRH test

- Suspected or known adrenocortical cancer or adenomas, as judged by ACTH values less than 10 pg/ml and adrenal mass

- Subjects with cyclic Cushing's syndrome defined by any measurement of Urinary Free Cortisol over the previous 2 months less than 2 N

- Children (age less than 18) and patients over 85 years

- Pregnant or lactating women. A urinary pregnancy test will be performed in women of childbearing potential unless they have a history of menopause prior to Cushing's syndrome or hysterectomy

- Life expectancy less than two months

- Surgery planned within 8 weeks after inclusion, especially bilateral adrenalectomy

- Uncontrolled diabetes (plasma glucose greater than 15.0 mmol/L (270 mg/L) and/or HbA1c greater than 10%)

- Uncontrolled hypertension (blood pressure greater than 180/110 mmHg)

- Recent (less than two weeks prior to inclusion) initiation of corrective treatments for depression

- Clinically significantly impaired cardiovascular function (e.g. stage IV cardiac failure)

- Severe liver disease (liver enzymes greater than or equal to 3 x the institutional upper limit of normal range)

- Severe renal impairment (serum creatinine greater than or equal to 2.2 mg/dl or creatinine clearance less than 30 ml/min)

- Severe hypokalemia (plasma K below 3.0 mmol/L)

- Uncontrolled severe active infection

- In women, known endometrial cancer, history of endometrial hyperplasia or vaginal bleeding of unknown cause

- Premenopausal women with hemorrhagic disorders or on anticoagulants

- Recent (less than two weeks prior to inclusion) initiation of or significant change in dose of anti-tumor therapy

- Previous treatment with approved or experimental steroidogenesis inhibitors, somatostatin analogues within one week of admission (eight weeks for patients on octreotide LAR or on lanreotide autogel)

- Plasma mitotane concentration greater than 5 microgram/ml

- Impaired mental capacity or markedly abnormal psychiatric evaluation that precludes informed consent

- Body weight over 136 kg, which is the limit for the tables used in the scanning areas

- Inherited porphyria

- Positive pregnancy test at inclusion

- Use of antiretroviral agents, midazolam, cabergoline, erythromycin, or grapefruit juice within two weeks of the study

Special Instructions:

Currently Not Provided

Keywords:

Cortisol

Cushing's Syndrome

Ectopic ACTH Secretion

Recruitment Keyword(s):

Cushing Syndrome

Condition(s):

Cushing's Syndrome

Investigational Drug(s):

Mifepristone

Investigational Device(s):

None

Intervention(s):

Drug: Mifepristone

Supporting Site:

Laboratoire HRA Pharma

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Bertagna X, Basin C, Picard F, Varet B, Bertagna C, Hucher M, Luton JP. Peripheral antiglucocorticoid action of RU 486 in man. Clin Endocrinol (Oxf). 1988 May;28(5):537-41.

Bertagna X, Escourolle H, Pinquier JL, Coste J, Raux-Demay MC, Perles P, Silvestre L, Luton JP, Strauch G. Administration of RU 486 for 8 days in normal volunteers: antiglucocorticoid effect with no evidence of peripheral cortisol deprivation. J Clin Endocrinol Metab. 1994 Feb;78(2):375-80.

Brazier JE, Harper R, Jones NM, O'Cathain A, Thomas KJ, Usherwood T, Westlake L. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ. 1992 Jul 18;305(6846):160-4.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Clinical Research Informatics, CC.

Search The Studies | Help | Questions |
Clinical Center Home | NIH Home

National Institutes of Health Clinical Center Bethesda, Maryland 20892. Last update: 01/30/2009