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

Phase 2
18 Years
85 Years
Not Enrolling
Cushing's Syndrome

Thank you

Trial Information

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

Between 10% and 20% of patients with hypercortisolism (Cushing's Syndrome) have tumoral
ectopic production of adrenocorticotropin hormone (ACTH) that causes cortisol excess. If an
ectopic tumor cannot be found or if surgery cannot be done, the treatment options include
medicines that reduce cortisol production and bilateral adrenalectomy. The available
medications that reduce cortisol production have important adverse effects and are not
effective in some patients and adrenalectomy leads to lifelong requirements for medical
hormone replacement. Thus, additional treatment options would be welcome. This study
evaluates a potential new medication for the treatment of these patients; mifepristone
blocks the effects of cortisol rather than decreasing its production. The purpose of this
study is to see whether this agent can improve diabetes or other symptoms of Cushing's
syndrome in subjects with ectopic ACTH secretion. Another purpose is to evaluate adverse
effects with this drug. Patients with presumed ectopic ACTH secretion and diabetes will
take mifepristone 600 mg daily by mouth, and the effect on diabetes and other symptoms of
Cushing's syndrome will be measured. Subjects will return to the hospital at 2, 3, 6, 9, and
12 months after starting mifepristione for evaluation of diabetes and other symptoms. The
agent will be available for up to 12 months for patients in whom it is effective.

Patients take mifepristone by mouth 3 times a day. Each dose will contain 200 mg. Patients
may remain in the hospital for all or part of the initial safety studies, every two weeks
for eight weeks. During this period blood pressure, glucose tolerance and blood chemistries
are measured and EKG and urinalysis done every two weeks. The mifepristone dose can be
decreased or stopped if there are adverse effects. When the mifepristone dose is stable for
eight weeks, patients will be re-evaluated. Patients then return to the hospital for
evaluations one month later and then every 3 months. Those who do well on the drug may
continue to take it for up to 12 months.

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


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


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


- 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

- 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

- 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

- Inherited porphyria

- Positive pregnancy test at inclusion

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

Type of Study:


Study Design:

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

Outcome Measure:

Change in glucose control.

Outcome Time Frame:

8 weeks at steady dose

Safety Issue:


Principal Investigator

Lynnette K Nieman, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)


United States: Federal Government

Study ID:




Start Date:

December 2006

Completion Date:

April 2012

Related Keywords:

  • Cushing's Syndrome
  • Cortisol
  • Cushing's Syndrome
  • Ectopic ACTH Secretion
  • Cushing Syndrome
  • Cushing Syndrome
  • Cardiac Complexes, Premature



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892