Does Serum-DXM Increase Diagnostic Accuracy of the Overnight DXM Suppression Test in the Work-up of Cushing's Syndrome? (DXM)

Evaluation of the Diagnostic Utility of Serum Dexamethasone Measurements in the Overnight 1mg Dexamethasone Suppression Test in Patients Investigated for Cushing's Syndrome and Incidentalomas

Background: The evaluation for hypercortisolism includes an overnight 1mg dexamethasone (DXM) suppression test. An important shortcoming is the diagnostic specificity of only 80%, which is likely due to inter-individual differences in gut absorption or metabolism of DXM.

Study hypothesis: The investigators hypothesize that serum-DXM measurements will increase the diagnostic accuracy of the overnight DXM-test in the work-up of hypercortisolism.

Aims: The primary aim of this prospective study is to evaluate if serum-DXM measured simultaneously with serum-cortisol in morning samples could increase the diagnostic accuracy this diagnostic test. There are several secondary aims. One is to estimate the prevalence and causes of unusual DXM absorption or metabolism. The investigators will also evaluate the feasibility and diagnostic accuracy of salivary DXM. Moreover, the diagnostic accuracy of midnight salivary cortisol and cortisone, and urinary cortisol, will be evaluated and compared.

Design: Levels of DXM in morning serum following an overnight DXM-test will be analyzed in patients under evaluation for hypercortisolism (including incidentalomas). A cut-off level to identify inadequate DXM concentrations in serum to suppress endogenous cortisol production will be established based on the negative tests. This cut-off level will then be applied in a retrospective analysis of the diagnostic accuracy of DXM-tests. This prospective study has a blinded design as the DXM measurements are disclosed after the end of the trial.

Study Overview

• Status: Unknown
• Conditions: Alcoholism; Obesity; Cushing's Syndrome; Adrenal Incidentalomas

• Study Type: Observational
• Enrollment (Anticipated): 300

Contacts and Locations

• Study Contact: Name: Grethe Åstrøm Ueland, MD; Phone Number: +4790950021; Email: geas@helse-bergen.no
• Study Contact Backup: Name: Paal Methli, MD; Phone Number: +4797677930

Study Locations

• Norway
  • Bergen, Norway, 5019
    • Not yet recruiting
    • Haukeland Universitetssykehus- Rusmedisinsk avdeling
    • Contact: Pia Synøve Kloster, Cand.med; Phone Number: 55975000
    • Sub-Investigator: Pia Synøve Kloster, Cand.med
  • Bergen, Norway, 5021
    • Recruiting
    • Haukeland Universitetssykehus- Endokrinologisk avdeling
    • Contact: Grethe Åstrøm Ueland, Doctor; Phone Number: +4790950021; Email: geas@helse-bergen.no
    • Contact: Hrafnkell Baldur Thordarsson, Doctor; Phone Number: +4755972995; Email: hraf@helse-bergen.no
    • Principal Investigator: Grethe Ueland, MD
    • Sub-Investigator: Hrafnkell Baldur Thordarsson, MD
    • Sub-Investigator: Eystein Husebye, Prof.Dr.Med
    • Sub-Investigator: Kristian Løvås, Prof.Dr.Med
  • Bergen, Norway, 5021
    • Recruiting
    • Institutt for farmakologi
    • Contact: Simon Steinar Hustad, Dr.Med
  • Bergen, Norway, 5096
    • Recruiting
    • Haukeland University Hospital- Hormonlaboratory
    • Contact: Grethe Åstrøm Ueland, Doctor; Phone Number: +4790950021; Email: geas@helse-bergen.no
    • Contact: Paal Methli, Doctor; Phone Number: +4797677930
    • Principal Investigator: Grethe Åstrøm Ueland, Doctor
    • Sub-Investigator: Paal Methli, Doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients at Haukeland University Hosptial, Bergen, Norway, under routine evaluation for hypercortisolism.Patients under evaluation for obeity at the overweight clinic, and Patients treated for alcohol abuse at the clinic for alcohol addicts at Haukeland University hospital.

Description

Inclusion Criteria:

• Age over 18 years
• Under investigation for hypercortisolism
• Able and willing to make informed consent

Exclusion Criteria:

• Use of systemic or local glucocorticoids

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients under investigation for hypercortisolism; Patients undergoing routine evaluation for hypercortisolism at Haukeland University Hospital, Bergen, Norway, will be asked to participate.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The difference (in percent) in false positive DXM-tests comparing the outcome of all tests with all tests excluding those with s-DXM below the the cut-off specified below.	The s-DXM cut-off will be defined a priori from ROC analysis on patients that inadequately suppress s-cortisol categorized as having Cushing's syndrome or being healthy. DXM, dexamethasone; DXM-test, short 1mg dexamethasone suppression test.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calculate the positive likelihood ratio [(1-sensitivity)/specificity] for the short DXM-test in the assessment of Cushing's syndrome (CS), after excluding those with s-DXM below the DXM cut-off specified in the primary endpoint.	Sensitivity = (Number of patients having CS with positive test / total number of patients with CS). Specificity = (Number of patients not having CS with negative test / total number of patients not having CS).	1 year
Calculate the negative likelihood ratio [(1-sensitivity)/specificity] for the short DXM-test in the assessment of Cushing's syndrome, after excluding those with s-DXM below the DXM cut-off specified in the primary endpoint.		1 year
Calculate the positive likelihood ratio [(1-sensitivity)/specificity] for midnight salivary cortisol in the assessment of Cushing's syndrome. All study cases are included in this analysis.		1 year
Calculate the negative likelihood ratio [(1-sensitivity)/specificity] for midnight salivary cortisol in the assessment of Cushing's syndrome. All study cases are included in this analysis.	A saliva cortisol cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.	1 year
Calculate the positive likelihood ratio [(1-sensitivity)/specificity] for midnight salivary cortisone in the assessment of Cushing's syndrome. All study cases are included in this analysis.	A saliva cortisone cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.	1 year
Calculate the negative likelihood ratio [(1-sensitivity)/specificity] for midnight salivary cortisone in the assessment of Cushing's syndrome. All study cases are included in this analysis.	A saliva cortisone cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.	1 year
Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM.		1 year
Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM, and saliva-cortisol replace serum-cortisol.		1 year
Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM and saliva-cortisone replace serum-cortisol.		1 year
Calculate the positive likelihood ratio [(1-sensitivity)/specificity] for creatinine-adjusted cortisol in morning spot urine in the assessment of Cushing's syndrome. All study cases are included in this analysis.	A cut-off level for creatinine-adjusted morning urine cortisol will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.	1 year
Calculate the negative likelihood ratio [(1-sensitivity)/specificity] for creatinine-adjusted cortisol in morning spot urine in the assessment of Cushing's syndrome. All study cases are included in this analysis.	A cut-off level for creatinine-adjusted morning urine cortisol will be defined a priori from ROC analysis on all patients with and without Cushing's Syndrome.	1 year
Compute a 95% confidence interval for morning s-DXM following overnight DXM-test in healthy subjects using parametric and non-parametric statistics.		1 year
Quantitatively and qualitatively describe the characteristics of patients with false positive DXM-test and true negative DXM-test based on a standard questionnaire scoring patient history, symptoms and clinical features.	Parametric descriptive statistics	1 year
Evaluate the dexamethasone metabolism in patients with obesity	We are evaluating if overweight patients metabolise Dexamethasone in the same way as normal weighted patients, by looking at the s-dexamethasone and s-cortisol level the day after 1 mg overnight Dexamethason suppression test.	1 year
Evaluate the dexamethasone metabolism in patients with alcohol abuse	We are evaluating if patients with alcohol abuse metabolise dexamethasone in the same way as normal patients, by looking at the s-dexamethasone and s-cortisol level the day after 1 mg overnight dexamethason suppression test.	1 year

Collaborators and Investigators

• Sponsor: Haukeland University Hospital
• Investigators: Study Chair: Grethe Åstrøm Ueland, MD, Haukeland University Hospital

Publications and helpful links

General Publications

• 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.
• Baid SK, Rubino D, Sinaii N, Ramsey S, Frank A, Nieman LK. Specificity of screening tests for Cushing's syndrome in an overweight and obese population. J Clin Endocrinol Metab. 2009 Oct;94(10):3857-64. doi: 10.1210/jc.2008-2766. Epub 2009 Jul 14.
• Carroll TB, Findling JW. The diagnosis of Cushing's syndrome. Rev Endocr Metab Disord. 2010 Jun;11(2):147-53. doi: 10.1007/s11154-010-9143-3.

Helpful Links

• Kortisol i spytt ved sykdom i binyrene
• Spyttprøver til kortisolmåling
• Endogent Cushing syndrom

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Anticipated): September 1, 2017
• Study Completion (Anticipated): September 1, 2017

Study Registration Dates

• First Submitted: November 15, 2011
• First Submitted That Met QC Criteria: January 3, 2012
• First Posted (Estimate): January 5, 2012

Study Record Updates

• Last Update Posted (Estimate): September 26, 2016
• Last Update Submitted That Met QC Criteria: September 23, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: hypercortisolism, dexamethasone, alcoholism,obesity.
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Alcohol-Related Disorders; Substance-Related Disorders; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Disease; Endocrine Gland Neoplasms; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenal Cortex Diseases; Alcoholism; Syndrome; Cushing Syndrome; Adrenocortical Adenoma
• Other Study ID Numbers: 2011/1810