Glucocorticoid Receptor Blockade With Mifepristone in Patients With Mild Adrenal Hypercortisolism

• ClinicalTrials.gov Identifier: NCT01990560
• Recruitment Status: Completed
• First Posted: November 21, 2013
• Results First Posted: March 2, 2018
• Last Update Posted: March 2, 2018
• Sponsor: Icahn School of Medicine at Mount Sinai
• Information provided by (Responsible Party): Alice C. Levine, Icahn School of Medicine at Mount Sinai

Tracking Information

• First Submitted Date: November 15, 2013
• First Posted Date: November 21, 2013
• Results First Submitted Date: October 18, 2017
• Results First Posted Date: March 2, 2018
• Last Update Posted Date: March 2, 2018
• Study Start Date: November 2013
• Actual Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 25, 2018)

• A1C Level [ Time Frame: Baseline, 3 months, and 6 months ]
  Change in hyperglycemia assessed by HbA1c, also known as glycated hemoglobin
• HOMA-IR [ Time Frame: Baseline and 6 months ]
  Change in hyperglycemia assessed by Homeostatic Model Assessment of Insulin Resistance, HOMA-IR (a validated assessment of insulin resistance). HOMA-IR = fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5.

Original Primary Outcome Measures (submitted: November 15, 2013)

hyperglycemia [ Time Frame: 6 months ]

Improvement in hyperglycemia - fasting glucose, HbA1c, HOMA-IR (a validated assessment of insulin resistance, HOMA-IR = (glucose md/dl x insulin mg/dl)/405)

Current Secondary Outcome Measures (submitted: January 25, 2018)

• Waist Circumference [ Time Frame: Baseline and 6 months ]
  Change in metabolic syndrome as assessed by waist circumference
• Body Mass Index (BMI) [ Time Frame: Baseline and 6 months ]
  Change in metabolic syndrome as assessed by BMI
• Fasting Lipid Profile [ Time Frame: Baseline and 6 months ]
  Change in metabolic syndrome as assessed by fasting lipid profile which includes Low-density lipoproteins ( LDL), High-density lipoproteins (HDL), and Triglycerides (Trigs) levels, and total cholesterol which is the sum of HDL plus LDL and 20% of trigs.
• Weight [ Time Frame: Baseline and 6 months ]
  Change in metabolic syndrome as assessed by weight
• CushingQoL [ Time Frame: Baseline and 6 months ]
  Change in Quality of Life - as assessed by the Cushing's Quality of Life questionnaire (CushingQoL). Patient completed questionnaire, 12 items, each scored on a 5 point score, resulting in a score of 12 (worst) to 60 (best) where higher scores indicate more favorable QOL.
• Nottingham Health Profile (NHP) [ Time Frame: Baseline and 6 months ]
  Change in Quality of Life as assessed by the Nottingham Health Profile (NHP) which is a patient reported questionnaire to measure a patient's view of their own health status. There are 6 sections (Energy level, Pain, Emotional Reaction, Sleep, Social Isolation, and Physical Abilities. All questions have only yes/no answer options and each section score is weighted so that the possible score range for any section is 0-100. The higher the score, the greater the number and severity of problems.
• Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Baseline and 6 months ]
  Change in Quality of Life as assessed by the Hospital Anxiety and Depression Scale (HADS). Questionnaire with 7 items for anxiety and 7 items for depression, each item is scored on a 4 point response 0 - 3, with full range from 0 to 42, with higher score indicating more severe anxiety or depression
• Quality of Life [ Time Frame: Baseline and 6 months ]
  Change in Quality of Life as assessed by the Beck Depression Inventory. a 21-question multiple choice, self-report inventory that is used for measuring the severity of anxiety. Scoring is from a 0 (not at all) to 3 (severe) with a total score range of 0-63. Higher total scores indicate more severe anxiety symptoms.
• State Trait Anxiety Inventory (STAI) [ Time Frame: Baseline and 6 months ]
  Change in Quality of Life - as assessed by the State Trait Anxiety Inventory (STAI). The State-Trait Anxiety Inventory both state and trait anxiety separately. Each type of anxiety has its own scale of 20 different questions that are scored and averaged. Total scores range from 20 to 80, with higher scores correlating with greater anxiety.

Original Secondary Outcome Measures (submitted: November 15, 2013)

• Metabolic Syndrome [ Time Frame: 6 months ]
  Improvement in metabolic syndrome - outcomes include cortisol, fasting lipid profile, weight, BMI (kg/m2), waist circumference (in centimeters), and blood pressure
• Quality of Life [ Time Frame: 6 months ]
  Improvement in Quality of Life - completion of 3 validated QoL questionnaires (Cushing's Quality of Life questionnaire (CushingQoL), Nottingham Health Profile (NHP), and Hospital Anxiety and Depression Scale (HADS)), and the visual analogue scale (VAS) to quantify appetite. Patients will also complete the Beck Depression Inventory and the State Trait Anxiety Inventory (STAI).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Glucocorticoid Receptor Blockade With Mifepristone in Patients With Mild Adrenal Hypercortisolism
• Official Title: Glucocorticoid Receptor Blockade With Mifepristone in Patients With Mild Adrenal Hypercortisolism

Brief Summary

The purpose of this study is to determine whether mifepristone is an effective treatment for hyperglycemia due to mild hypercortisolism.

• To test the hypothesis that GR blockade with mifepristone will decrease the severity of metabolic syndrome features as measured by waist circumference, lipid profile, body mass index, blood pressure and insulin resistance, measured by HOMA-IR score.
• To test the hypothesis that GR blockade with mifepristone will improve QoL, depression and anxiety scores, measured by validated assessments, in patients with mild hypercortisolism.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Mild Hypercortisolism

Intervention

Drug: Mifepristone

All patients in the study will receive daily Mifepristone for 6 months and primary and secondary outcomes will be assessed before and after the 6 month treatment period

Other Name: Korlym

Study Arms

Experimental: Mifepristone

Mifepristone 300mg tablets taken once daily with dose increase of no more than 300mg once monthly and to a maximum dose of 1200mg daily as indicated by symptom response

Intervention: Drug: Mifepristone

Publications *

• Young WF Jr. Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am. 2000 Mar;29(1):159-85, x. doi: 10.1016/s0889-8529(05)70122-5.
• Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev. 2004 Apr;25(2):309-40. doi: 10.1210/er.2002-0031.
• Tauchmanova L, Rossi R, Biondi B, Pulcrano M, Nuzzo V, Palmieri EA, Fazio S, Lombardi G. Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab. 2002 Nov;87(11):4872-8. doi: 10.1210/jc.2001-011766.
• Terzolo M, Pia A, Ali A, Osella G, Reimondo G, Bovio S, Daffara F, Procopio M, Paccotti P, Borretta G, Angeli A. Adrenal incidentaloma: a new cause of the metabolic syndrome? J Clin Endocrinol Metab. 2002 Mar;87(3):998-1003. doi: 10.1210/jcem.87.3.8277.
• Garrapa GG, Pantanetti P, Arnaldi G, Mantero F, Faloia E. Body composition and metabolic features in women with adrenal incidentaloma or Cushing's syndrome. J Clin Endocrinol Metab. 2001 Nov;86(11):5301-6. doi: 10.1210/jcem.86.11.8059.
• Feelders RA, Hofland LJ. Medical treatment of Cushing's disease. J Clin Endocrinol Metab. 2013 Feb;98(2):425-38. doi: 10.1210/jc.2012-3126. Epub 2013 Jan 23.
• Lambert JK, Goldberg L, Fayngold S, Kostadinov J, Post KD, Geer EB. Predictors of mortality and long-term outcomes in treated Cushing's disease: a study of 346 patients. J Clin Endocrinol Metab. 2013 Mar;98(3):1022-30. doi: 10.1210/jc.2012-2893. Epub 2013 Feb 7.
• Neary NM, Booker OJ, Abel BS, Matta JR, Muldoon N, Sinaii N, Pettigrew RI, Nieman LK, Gharib AM. Hypercortisolism is associated with increased coronary arterial atherosclerosis: analysis of noninvasive coronary angiography using multidetector computerized tomography. J Clin Endocrinol Metab. 2013 May;98(5):2045-52. doi: 10.1210/jc.2012-3754. Epub 2013 Apr 4.
• Debono M, Chadarevian R, Eastell R, Ross RJ, Newell-Price J. Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol: a pilot study. PLoS One. 2013;8(4):e60984. doi: 10.1371/journal.pone.0060984. Epub 2013 Apr 5.
• Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-40. doi: 10.1210/jc.2008-0125. Epub 2008 Mar 11.
• Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord. 2000 Jan;24(1):38-48. doi: 10.1038/sj.ijo.0801083.
• Parker BA, Sturm K, MacIntosh CG, Feinle C, Horowitz M, Chapman IM. Relation between food intake and visual analogue scale ratings of appetite and other sensations in healthy older and young subjects. Eur J Clin Nutr. 2004 Feb;58(2):212-8. doi: 10.1038/sj.ejcn.1601768.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 29, 2016): 8
• Original Estimated Enrollment (submitted: November 15, 2013): 20
• Actual Study Completion Date: September 2016
• Actual Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• >18 years of age
• Incidentally noted adrenal nodule <4 cm with benign imaging characteristics
• Evidence of mild hypercortisolism
• Evidence of diabetes or abnormal glucose tolerance

Exclusion Criteria:

• contraindication to mifepristone
• Indication for unilateral adrenalectomy
• Evidence of other adrenal hormone hypersecretion
• lactating mothers
• women of childbearing age unwilling to use an effective, nonhormonal form of contraception

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01990560
• Other Study ID Numbers: GCO 13-1061
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Alice C. Levine, Icahn School of Medicine at Mount Sinai
• Original Responsible Party: Same as current
• Current Study Sponsor: Icahn School of Medicine at Mount Sinai
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Alice C Levine, MD; Icahn School of Medicine at Mount Sinai

• PRS Account: Icahn School of Medicine at Mount Sinai
• Verification Date: January 2018