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

September 30, 2019 updated by: HRA Pharma

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
18

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Bordeaux, France
        • CHU de Bordeaux Hôpital Haut Lévêque
      • Grenoble, France
        • C.H.U Albert Michallon
      • Le Kremlin-Bicêtre, France
        • C.H.U. de Bicetre
      • Lille, France
        • CHRU de Lille
      • Marseille, France
        • Hôpital de la Timone
      • Paris, France
        • AP-HP, Hopital Cochin Pavillon CORNIL
      • Toulouse, France
        • CHU de TOULOUSE
  • Germany
      • Wuerzbug, Germany
        • University of Wuerzburg
  • Italy
      • Napoli, Italy
        • Università degli Studi
      • Orbassano, Italy
        • University of Turin
      • Padova, Italy
        • University of Padova
  • Netherlands
      • Eindhoven, Netherlands
        • Internal Medicine Endocrinology
      • Groningen, Netherlands
        • University Hosiptal of Groningen
      • Rotterdam, Netherlands
        • Erasmus Medical Center
  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Prospective, open-label, study of mifepristone
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
Singe dose

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Glycemic Disorders Improved or Normalized
Time Frame: 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)
8 weeks at steady dose

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Features of Cushing's Syndrome
Time Frame: 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
8 weeks at steady dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
HRA Pharma

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 15, 2007

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 4, 2012

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 4, 2012

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 12, 2007

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 12, 2007

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 15, 2007

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 11, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 30, 2019

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 070008
  • 07-CH-0008

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