Back to resultsProspective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion
Primary Purpose
Cushing's Syndrome
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Mifepristone
Sponsored by
About this trial
This is an interventional treatment trial for Cushing's Syndrome focused on measuring Cortisol, Cushing's Syndrome, Ectopic ACTH Secretion, Cushing Syndrome
Eligibility Criteria
- INCLUSION CRITERIA:
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.
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
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
- CHU de Bordeaux Hopital Haut Leveque
- C.H.U Albert Michallon
- C.H.U. de Bicetre
- CHRU de Lille
- Hopital de la Timone
- AP-HP, Hopital Cochin Pavillon CORNIL
- CHU de Toulouse
- University of Wuerzburg
- Universita Degli Studi
- University of Turin
- University of Padova
- Internal Medicine Endocrinology
- University Hosiptal of Groningen
- Erasmus Medical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Prospective, open-label, study of mifepristone
Arm Description
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.
Outcomes
Primary Outcome Measures
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)
Secondary Outcome Measures
Features of Cushing's Syndrome
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00422201
Brief Title
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion
Official Title
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion
Study Type
Interventional
2. Study Status
Record Verification Date
September 2019
Overall Recruitment Status
Terminated
Study Start Date
May 15, 2007 (Actual)
Primary Completion Date
April 4, 2012 (Actual)
Study Completion Date
April 4, 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
HRA Pharma
4. Oversight
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cushing's Syndrome
Keywords
Cortisol, Cushing's Syndrome, Ectopic ACTH Secretion, Cushing Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Prospective, open-label, study of mifepristone
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Mifepristone
Intervention Description
Singe dose
Primary Outcome Measure Information:
Title
Glycemic Disorders Improved or Normalized
Description
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)
Time Frame
8 weeks at steady dose
Secondary Outcome Measure Information:
Title
Features of Cushing's Syndrome
Description
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
Time Frame
8 weeks at steady dose
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA:
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.
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lynnette K Nieman, M.D.
Organizational Affiliation
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
CHU de Bordeaux Hopital Haut Leveque
City
Bordeaux
Country
France
Facility Name
C.H.U Albert Michallon
City
Grenoble
Country
France
Facility Name
C.H.U. de Bicetre
City
Le Kremlin-Bicêtre
Country
France
Facility Name
CHRU de Lille
City
Lille
Country
France
Facility Name
Hopital de la Timone
City
Marseille
Country
France
Facility Name
AP-HP, Hopital Cochin Pavillon CORNIL
City
Paris
Country
France
Facility Name
CHU de Toulouse
City
Toulouse
Country
France
Facility Name
University of Wuerzburg
City
Wuerzbug
Country
Germany
Facility Name
Universita Degli Studi
City
Napoli
Country
Italy
Facility Name
University of Turin
City
Orbassano
Country
Italy
Facility Name
University of Padova
City
Padova
Country
Italy
Facility Name
Internal Medicine Endocrinology
City
Eindhoven
Country
Netherlands
Facility Name
University Hosiptal of Groningen
City
Groningen
Country
Netherlands
Facility Name
Erasmus Medical Center
City
Rotterdam
Country
Netherlands
12. IPD Sharing Statement
Citations:
PubMed Identifier
3214945
Citation
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.
Results Reference
background
PubMed Identifier
8106625
Citation
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.
Results Reference
background
PubMed Identifier
1285753
Citation
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.
Results Reference
background
Links:
URL
http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2007-CH-0008.html
Description
NIH Clinical Center Detailed Web Page
Learn more about this trial
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion
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