A Study of the Efficacy and Safety of CORLUX in the Treatment of Endogenous Cushing's Syndrome (SEISMIC)

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ClinicalTrials.gov Identifier: NCT00569582

Recruitment Status : Completed

First Posted : December 7, 2007

Results First Posted : May 28, 2012

Last Update Posted : August 22, 2013

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Sponsor:

Information provided by (Responsible Party):

Corcept Therapeutics

Study Type	Interventional
Study Design	Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Cushing's Syndrome
Intervention	Drug: mifepristone
Enrollment	50

Participant Flow

Recruitment Details	24 week multicenter, open-label trial after failed multimodality therapy at 14 U.S. academic medical centers and three private research centers.
Pre-assignment Details	Adults with endogenous Cushing's Syndrome associated with either type 2 diabetes mellitus/impaired glucose tolerance or a diagnosis of hypertension.


Arm/Group Title	Mifepristone
Arm/Group Description	Mifepristone was administered at do...
Arm/Group Description	Mifepristone was administered at doses of 300-1200 mg daily.
Period Title: Overall Study
Started	50
Completed	34
Not Completed	16
Reason Not Completed
Withdrawal by Subject	5
Death	2
Adverse Event	7
Subject was too ill to travel.	1
Subject was non-compliant.	1

Baseline Characteristics

Arm/Group Title		Mifepristone
Arm/Group Description		Mifepristone was administered at do...
Arm/Group Description		Mifepristone was administered at doses of 300-1200 mg daily.
Overall Number of Baseline Participants		50
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	50 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	46 92.0%
	>=65 years	4 8.0%
Age Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	50 participants
		45.4 (11.85)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	50 participants
	Female	35 70.0%
	Male	15 30.0%
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	50 participants
United States		50

Outcome Measures

1.Primary Outcome


Title	Improvement in Diabetes and/or Glucose Intolerance.
Description	Responder is defined as subject with a decrease greater than or equal ...
Description	Responder is defined as subject with a decrease greater than or equal to 25% in area under the curve for glucose on 2-hour oral glucose test from baseline to week 24 or last visit, for Cushing's patients with type-2 diabetes mellitus/impaired glucose tolerance.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Patients with at least 30 days of dosing.


Arm/Group Title	Mifepristone
Arm/Group Description:	Mifepristone was administered at do...
Arm/Group Description:	Mifepristone was administered at doses of 300-1200 mg daily.
Overall Number of Participants Analyzed	25
Measure Type: Number Unit of Measure: participants
	15

2.Primary Outcome


Title	Decrease in Diastolic Blood Pressure.
Description	Responder is defined as subject with a decrease greater than or equal ...
Description	Responder is defined as subject with a decrease greater than or equal to 5mm Hg in diastolic blood pressure from baseline to week 24 or last visit.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Mifepristone
Arm/Group Description:	Mifepristone was administered at do...
Arm/Group Description:	Mifepristone was administered at doses of 300-1200 mg daily.
Overall Number of Participants Analyzed	21
Measure Type: Number Unit of Measure: participants
	8

Adverse Events

Time Frame	24 weeks
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Mifepristone
Arm/Group Description	Mifepristone was administered at do...
Arm/Group Description	Mifepristone was administered at doses of 300-1200 mg daily.
All-Cause Mortality
	Mifepristone
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events Serious Adverse Events
	Mifepristone
	Affected / at Risk (%)	# Events
Total	16/50 (32.00%)
Cardiac disorders
Cardiomyopathy ^† 1	1/50 (2.00%)	1
Angina Pectoris ^† 1	1/50 (2.00%)	1
Endocrine disorders
Adrenal Insufficiency ^† 1	1/50 (2.00%)	1
Gastrointestinal disorders
Gastritis Erosive ^† 1	1/50 (2.00%)	1
Vomiting ^† 1 [1]	1/50 (2.00%)	1
General disorders
Asthenia ^† 1	1/50 (2.00%)	2
Infections and infestations
Legionella pneumonia ^† 1	1/50 (2.00%)	1
Sinusitis ^† 1	1/50 (2.00%)	1
Subcutaneous Abscess ^† 1	1/50 (2.00%)	1
Injury, poisoning and procedural complications
Foot Fracture ^† 1	1/50 (2.00%)	1
Investigations
Blood Potassium Decreased ^† 1	1/50 (2.00%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
adrenal carcinoma ^† 1	2/50 (4.00%)	2
neoplasm progression ^† 1	1/50 (2.00%)	1
neuroendocrine carcinoma ^† 1	1/50 (2.00%)	1
Nervous system disorders
Intracranial Aneurysm ^† 1	1/50 (2.00%)	1
Psychiatric disorders
Confusional State ^† 1	1/50 (2.00%)	1
Renal and urinary disorders
Renal Failure Acute ^† 1	1/50 (2.00%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^† 1	1/50 (2.00%)	2
Respiratory Failure ^† 1	2/50 (4.00%)	2
Pulmonary Oedema ^† 1	1/50 (2.00%)	1
Pulmonary Embolism ^† 1	1/50 (2.00%)	1
Vascular disorders
Orthostatic Hypotension ^† 1	1/50 (2.00%)	1
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MEDRA [1] severe
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Mifepristone
	Affected / at Risk (%)	# Events
Total	49/50 (98.00%)
Endocrine disorders
Cushing's syndrome ^† 1	4/50 (8.00%)	6
Eye disorders
Vision blurred ^† 1	4/50 (8.00%)	5
Gastrointestinal disorders
Nausea ^† 1	24/50 (48.00%)	40
Vomiting ^† 1	13/50 (26.00%)	21
Dry mouth ^† 1	9/50 (18.00%)	12
Diarrhoea ^† 1	6/50 (12.00%)	8
Constipation ^† 1	5/50 (10.00%)	5
Gastrooesophageal reflux disease ^† 1	4/50 (8.00%)	4
General disorders
Fatigue ^† 1	24/50 (48.00%)	37
Oedema peripheral ^† 1	13/50 (26.00%)	31
Pain ^† 1	7/50 (14.00%)	9
Asthenia ^† 1 [1]	3/50 (6.00%)	5
Malaise ^† 1	3/50 (6.00%)	4
Oedema ^† 1	3/50 (6.00%)	6
Pitting oedema ^† 1	3/50 (6.00%)	4
Thirst ^† 1	3/50 (6.00%)	3
Infections and infestations
Sinusitis ^† 1	7/50 (14.00%)	9
Nasopharyngitis ^† 1	6/50 (12.00%)	10
Urinary tract infection ^† 1	4/50 (8.00%)	5
Upper respiratory tract infection ^† 1	3/50 (6.00%)	5
Injury, poisoning and procedural complications
Contusion ^† 1	3/50 (6.00%)	4
Investigations
Blood potassium decreased ^† 1	17/50 (34.00%)	27
Thyroid function test abnormal ^† 1	9/18 (50.00%)	11
Blood triglycerides increased ^† 1	4/50 (8.00%)	5
Metabolism and nutrition disorders
Decreased appetite ^† 1	10/20 (50.00%)	12
Anorexia ^† 1	5/50 (10.00%)	6
Hypoglycaemia ^† 1	3/50 (6.00%)	4
Hypertension ^† 1	12/50 (24.00%)	14
Hot flush ^† 1	3/50 (6.00%)	3
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	15/50 (30.00%)	20
Back pain ^† 1	8/50 (16.00%)	9
Myalgia ^† 1	7/50 (14.00%)	11
Pain in extremity ^† 1	6/50 (12.00%)	6
Muscular weakness ^† 1	4/50 (8.00%)	6
Flank pain ^† 1	3/50 (6.00%)	3
Musculoskeletal chest pain ^† 1	3/50 (6.00%)	4
Nervous system disorders
Headache ^† 1	22/50 (44.00%)	40
Dizziness ^† 1	11/50 (22.00%)	20
Somnolence ^† 1	5/50 (10.00%)	7
Psychiatric disorders
Anxiety ^† 1	5/50 (10.00%)	12
Insomnia ^† 1	3/50 (6.00%)	5
Renal and urinary disorders
Pollakiuria ^† 1	3/50 (6.00%)	3
Reproductive system and breast disorders
Vaginal haemorrhage ^† 1	4/50 (8.00%)	4
Metrorrhagia ^† 1	3/50 (6.00%)	8
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^† 1 [2]	8/50 (16.00%)	11
Pharyngolaryngeal pain ^† 1	4/50 (8.00%)	4
Cough ^† 1	3/50 (6.00%)	4
Skin and subcutaneous tissue disorders
Dry skin ^† 1	4/50 (8.00%)	5
Ecchymosis ^† 1	4/50 (8.00%)	4
Acne ^† 1	3/50 (6.00%)	5
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MEDRA [1] mild [2] mild or moderate

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Medical Director
Organization:	Corcept Therapeutics
Phone:	650-327-3270
EMail:	info@corcept.com

Publications of Results:

Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C; SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012 Jun;97(6):2039-49. doi: 10.1210/jc.2011-3350. Epub 2012 Mar 30.

Other Publications:

Sartor O, Cutler GB Jr. Mifepristone: treatment of Cushing's syndrome. Clin Obstet Gynecol. 1996 Jun;39(2):506-10. doi: 10.1097/00003081-199606000-00024.

Johanssen S, Allolio B. Mifepristone (RU 486) in Cushing's syndrome. Eur J Endocrinol. 2007 Nov;157(5):561-9. doi: 10.1530/EJE-07-0458.

Morris D, Grossman A. The medical management of Cushing's syndrome. Ann N Y Acad Sci. 2002 Sep;970:119-33. doi: 10.1111/j.1749-6632.2002.tb04418.x.

Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR, Feldman D. Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486). J Clin Endocrinol Metab. 2001 Aug;86(8):3568-73. doi: 10.1210/jcem.86.8.7740.

Agarwai MK. The antiglucocorticoid action of mifepristone. Pharmacol Ther. 1996;70(3):183-213. doi: 10.1016/0163-7258(96)00016-2.

Miller JW, Crapo L. The medical treatment of Cushing's syndrome. Endocr Rev. 1993 Aug;14(4):443-58. doi: 10.1210/edrv-14-4-443. No abstract available.

Nieman LK, Chrousos GP, Kellner C, Spitz IM, Nisula BC, Cutler GB, Merriam GR, Bardin CW, Loriaux DL. Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486. J Clin Endocrinol Metab. 1985 Sep;61(3):536-40. doi: 10.1210/jcem-61-3-536.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Fein HG, Vaughan TB 3rd, Kushner H, Cram D, Nguyen D. Sustained weight loss in patients treated with mifepristone for Cushing's syndrome: a follow-up analysis of the SEISMIC study and long-term extension. BMC Endocr Disord. 2015 Oct 27;15:63. doi: 10.1186/s12902-015-0059-5.

Fleseriu M, Findling JW, Koch CA, Schlaffer SM, Buchfelder M, Gross C. Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. J Clin Endocrinol Metab. 2014 Oct;99(10):3718-27. doi: 10.1210/jc.2014-1843. Epub 2014 Jul 11.

Wallia A, Colleran K, Purnell JQ, Gross C, Molitch ME. Improvement in insulin sensitivity during mifepristone treatment of Cushing syndrome: early and late effects. Diabetes Care. 2013 Sep;36(9):e147-8. doi: 10.2337/dc13-0246. No abstract available.

Layout table for additonal information

Responsible Party:	Corcept Therapeutics
ClinicalTrials.gov Identifier:	NCT00569582
Other Study ID Numbers:	C-1073-400
First Submitted:	December 5, 2007
First Posted:	December 7, 2007
Results First Submitted:	April 4, 2012
Results First Posted:	May 28, 2012
Last Update Posted:	August 22, 2013

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