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.

• Mifepristone (Drug): Singe dose

Primary outcomes

• Glycemic Disorders Improved or Normalized [8 weeks at steady dose]: Criteria for improvement or normalization of glycemic disorders: A. For diabetic patients (known or diagnosed at pre-inclusion visit) * Decrease in HbA1c > 0.3% B. For patients with IGT * Normalization of OGTT (2-hour glucose plasma level after 75 g OGTT < 7.8 mmol/L (140 mg/dL) D. For patients with IFG If impaired fasting glucose is also associated with impaired glucose tolerance during OGTT at pre-inclusion: \- Normalization of OGTT (2-hour glucose plasma level after 75 g OGTT < 7.8 mmol/L (140 mg/dL) If impaired fasting glycemia is associated with normal OGTT at pre-inclusion (except at T0): \- Normalization of fasting plasma glucose (fasting plasma glucose < 5.5 mmol/L (100 mg/dL)

Secondary outcomes

• Features of Cushing's Syndrome [8 weeks at steady dose]: Criteria for secondary glycemic disorder improvement of clinical symptoms attributable to the Cushing's syndrome A. For diabetic patients * Improvement of the following parameters: glycemic profile, fasting blood glucose, fructosamine, 2-hour OGTT (for diabetics diagnosed at screening) * Number of anti-diabetics treatment or dose of anti-diabetics treatment for diabetic patients already on diabetes treatment at inclusion * Doses of insulin for insulin-treated patients B. For patients with IGT * HbA1c * Fructosamine C. For patients with IFG * HbA1c * Fructosamine D. For all patients * Fasting plasma insulin * Area Under the Curve of OGTT results when OGTT performed * HOMA index

Sex: All, ages: 18 Years to 85 Years

* 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

Participant flow

Outcome results

• Glycemic Disorders Improved or Normalized (Primary), Number, participants: Mifepristone 2
• Features of Cushing's Syndrome (Secondary), Number, participants: Prospective, Open-label, Study of Mifepristone 2

Adverse events

Time frame: Adverse events were collected from enrollment to the end of the study ie up to 12 months.

Serious adverse events by term

Other adverse events by term

25 more terms not shown.

Limitations and caveats: As a consequence of the premature study end, analyses performed were primarily descriptive due to the reduced number of enrolled and completed patients.

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• Lynnette K Nieman, M.D., Principal investigator, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)