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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

Official Title: 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

Brief Summary:

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.

Detailed Summary:
Sponsor: Haukeland University Hospital

Current Primary Outcome: 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. [ Time Frame: 1 year ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• 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. [ Time Frame: 1 year ]

  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).

• 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 1 year ]
  A saliva cortisol cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.
• 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. [ Time Frame: 1 year ]
  A saliva cortisone cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.
• 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. [ Time Frame: 1 year ]
  A saliva cortisone cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.
• Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM. [ Time Frame: 1 year ]
• Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM, and saliva-cortisol replace serum-cortisol. [ Time Frame: 1 year ]
• Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM and saliva-cortisone replace serum-cortisol. [ Time Frame: 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. [ Time Frame: 1 year ]
  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.
• 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. [ Time Frame: 1 year ]
  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.
• Compute a 95% confidence interval for morning s-DXM following overnight DXM-test in healthy subjects using parametric and non-parametric statistics. [ Time Frame: 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. [ Time Frame: 1 year ]
  Parametric descriptive statistics
• Evaluate the dexamethasone metabolism in patients with obesity [ Time Frame: 1 year ]
  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.
• Evaluate the dexamethasone metabolism in patients with alcohol abuse [ Time Frame: 1 year ]
  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.

Original Secondary Outcome:

• 1.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. [ Time Frame: 1 year ]

  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).

• 2.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. [ Time Frame: 1 year ]
• 3.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. [ Time Frame: 1 year ]
• 4.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. [ Time Frame: 1 year ]
  A saliva cortisol cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.
• 5.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. [ Time Frame: 1 year ]
  A saliva cortisone cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.
• 6.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. [ Time Frame: 1 year ]
  A saliva cortisone cut-off level will be defined a priori from ROC analysis on all patients with and without Cushing's syndrome.
• 7.Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM. [ Time Frame: 1 year ]
• 8.Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM, and saliva-cortisol replace serum-cortisol. [ Time Frame: 1 year ]
• 9.Identical to primary endpoint, but saliva-DXM measurements replace serum-DXM and saliva-cortisone replace serum-cortisol. [ Time Frame: 1 year ]
• 10.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. [ Time Frame: 1 year ]
  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.
• 11.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. [ Time Frame: 1 year ]
  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.
• 12.Compute a 95% confidence interval for morning s-DXM following overnight DXM-test in healthy subjects using parametric and non-parametric statistics. [ Time Frame: 1 year ]
• 13.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. [ Time Frame: 1 year ]
  Parametric descriptive statis

Information By: Haukeland University Hospital

Dates:
Date Received: November 15, 2011
Date Started: October 2011
Date Completion: September 2017
Last Updated: September 23, 2016
Last Verified: September 2016