Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion
Condition: Cushing's Syndrome
MeSH terms: Cardiac Complexes, Premature; Cushing Syndrome; Syndrome
Intervention: Mifepristone
Intervention description: Singe dose
Intervention MeSH terms: Mifepristone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Cortisol; Cushing's Syndrome; Ectopic ACTH Secretion; Cushing Syndrome

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 85 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.
    

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