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

NCT00422201 | Terminated Phase 2 Results

• 2 other identifiers: 07000807-CH-0008
• Study Type: interventional
• Target: 18
• Locations: 5 countries
• Sites: 15

Brief 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.

Conditions

Cushing's Syndrome

Keywords

Cortisol; Cushing's Syndrome; Ectopic ACTH Secretion; Cushing Syndrome

Outcome Measures

Primary Outcomes (1)

• Glycemic Disorders Improved or Normalized

  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)

  8 weeks at steady dose

Secondary Outcomes (1)

• Features of Cushing's Syndrome

  8 weeks at steady dose

Study Arms (1)

Prospective, open-label, study of mifepristone

EXPERIMENTAL

Eligible subjects will start study treatment at the dose of 600 mg/day (given as one 200 mg tablet tid, per os). Total duration of treatment will not exceed 12 months. At the end of 12-month treatment, investigators may petition to extend treatment on a case-by-case basis.

Drug: Mifepristone

Interventions

Mifepristone DRUG

Singe dose

Prospective, open-label, study of mifepristone

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects will be included if they have ALL of the three following criteria:
• Hypercortisolism from Cushing's syndrome caused by ACTH ectopic secretion
• AND
• Glycemic disorder that is considered to be caused or worsened by the hypercortisolism
• AND
• At least one symptom attributable to the Cushing's syndrome.

You may not qualify if:

• 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
• 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)
• 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

Sponsors & Collaborators

• HRA Pharma: lead

Study Sites (15)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

CHU de Bordeaux Hopital Haut Leveque

Bordeaux, France

Location

C.H.U Albert Michallon

Grenoble, France

Location

C.H.U. de Bicetre

Le Kremlin-Bicêtre, France

Location

CHRU de Lille

Lille, France

Location

Hopital de la Timone

Marseille, France

Location

AP-HP, Hopital Cochin Pavillon CORNIL

Paris, France

Location

CHU de Toulouse

Toulouse, France

Location

University of Wuerzburg

Wuerzbug, Germany

Location

Universita Degli Studi

Napoli, Italy

Location

University of Turin

Orbassano, Italy

Location

University of Padova

Padua, Italy

Location

Internal Medicine Endocrinology

Eindhoven, Netherlands

Location

University Hosiptal of Groningen

Groningen, Netherlands

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

Related Publications (3)

• 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. doi: 10.1111/j.1365-2265.1988.tb03688.x.

  PMID: 3214945 BACKGROUND

• 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. doi: 10.1210/jcem.78.2.8106625.

  PMID: 8106625 BACKGROUND

• 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. doi: 10.1136/bmj.305.6846.160.

  PMID: 1285753 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Cushing Syndrome; ACTH Syndrome, Ectopic

Interventions

Mifepristone

Condition Hierarchy (Ancestors)

Adrenocortical Hyperfunction; Adrenal Gland Diseases; Endocrine System Diseases; Paraneoplastic Endocrine Syndromes; Paraneoplastic Syndromes; Neoplasms

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

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.

Results Point of Contact

• Title: Head of Clinical Research
• Organization: HRA Pharma

s.durand@hra-pharma.com

0033140331130

Study Officials

• Lynnette K Nieman, M.D.

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2007
• First Posted: January 15, 2007
• Study Start: May 15, 2007
• Primary Completion: April 4, 2012
• Study Completion: April 4, 2012
• Last Updated: October 11, 2019
• Results First Posted: October 14, 2013

Record last verified: 2019-09

Locations

NL (3); US (1); DE (1); FR (7); IT (3)