Effects of Metyrapone in Patients With Hypercortisolism

Study Overview
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Brief Summary
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The aims of the present study are to evaluate in patients with mild hypercortisolism the effect of metyrapone treatment on glycometabolic control, blood pressure, thrombotic risk parameters, lipid profile, bone turnover markers, mental health and cortisol circadian rhythm.

Detailed Description
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This open prospective observational study will include patients with mild hypercortisolism of both adrenal and pituitary origin not candidate for surgery. Patients taking metyrapone since less than a week will be followed up for 24 weeks. During this period of time, patients will be re-evaluated as far as blood pressure control, glycometabolic control, thrombotic risk parameters, lipid profile, bone turnover markers and cortisol circadian rhythm is concerned.

Official Title
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Metabolic, Pressor and Neuropsychological Effects of Metyrapone Treatment in Patients With Hypercortisolism

Conditions
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Hypercortisolism

Intervention / Treatment
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* Drug: Metyrapone Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with mild Cushing's Syndrome not candidate for surgery Current therapy with metyrapone since less than 1 week Cortisol levels at 08:00 after 1 mg-overnight dexamethasone suppression test (1mgDST) >1.8 μg/dL Confirmed with 2 mg two days dexamethasone suppression test (2mgx2dDST) Presence of at least one out of the following conditions: type 2 diabetes mellitus, impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), arterial hypertension, bone mineral density (BMD) Z-score < -2.0 and/or fragility fracture at any skeletal site Stable anti-hypertensive therapies and blood pressure (BP) levels in the month before enrolment Stable anti-diabetic therapies and glycometabolic control during the month before enrolment Stable body weight during the month before enrolment Exclusion Criteria: Signs and/or symptoms of overt hypercortisolism (striae rubrae, moon facies, easy bruising, buffalo hump, hypertrichosis) Malignant hypertension and/or BP <200/120 mmHg Severe hyperglycemia (i.e. FG >350 mg/dL) Urinary free cortisol (UFC) higher than 1.5 fold the upper normal range Presence of pheochromocytoma or primary hyperaldosteronism Possible adrenal metastases or radiological features suggestive for adrenal malignancy (i.e. not homogeneous pattern, necrosis, calcifications, irregular margins, local invasion and high density at computed tomography) Congenital adrenal hyperplasia Intake of drugs influencing cortisol metabolism and/or secretion Women in child-bearing age Patients with body mass index (BMI) >35 kg/m2

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| metyrapone treatment<br>hypercortisolemic patients taking metyrapone since less than a week (usually 250 mg/day, maximum dose 6000 mg/day) | Drug: Metyrapone Capsules<br>* Exposure to 24 weeks of treatment with metyrapone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) at baseline who achieved fasting glucose <100 mg/dL and/or 2-hour glucose <140 mg/dL after a 75 gr-oral glucose tolerance test, respectively |  | Baseline, 12 weeks, 24 weeks | 
| Proportion of type 2 diabetes mellitus (T2DM) patients with HbA1c ≥7% at baseline who achieved HbA1c <7% |  | Baseline, 12 weeks, 24 weeks | 
| Proportion of IFG-IGT and T2DM patients with any decrease in dose of antidiabetic drugs |  | Baseline, 12 weeks, 24 weeks | 
| Proportion of patients without optimal blood pressure (BP) levels at baseline who achieve an optimal BP control | The optimal targets for BP levels in hypertensive patients are: in non-diabetic patients: <140/90 if ≥65 years, <130/80 if <65 years; in diabetic patients: <140/80 mmHg if ≥65 years and <130/80 if <65 years BP levels will be measured with arterial blood pressure monitoring (ABPM) | Baseline, 12 weeks, 24 weeks | 
| Proportion of patients with a mean BP reduction of ≥5 mm Hg | BP levels will be measured with arterial blood pressure monitoring (ABPM) | Baseline, 12 weeks, 24 weeks | 
| Proportion of hypertensive patients with any decrease in dose of anti-hypertensive drugs |  | Baseline, 12 weeks, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of thrombotic risk parameters | The thrombotic risk profile will be evaluated by measuring C-Protein, S-Protein, coagulation factor VIII and anti-thrombin III levels | Baseline, 12 and 24 weeks | 
| Changes of lipid profile | The lipid profile modifications will be evaluated by measuring total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides | Baseline, 12 and 24 weeks | 
| Changes of bone turnover markers | The bone turnover changes will be assessed by measuring calcium, phosphorous, osteocalcin (OC), carboxy-terminal cross-linked telopeptide of type I collagen (CTX) and 24-h urinary calcium/creatinine ratio | Baseline, 12 and 24 weeks | 
| Normalization of cortisol circadian rhythm | The cortisol circadian rhythm will be assessed by salivary cortisol levels determination (at 8 AM, 12 AM, 4 PM, 8 PM and 11 PM). | baseline, 4 weeks, 12 weeks, 16 weeks, 24 weeks. | 
| Amelioration of psychological symptoms | Psychological symptoms wil be evaluated with Beck Depression Inventory-II (BDI-II), a 21-item self-administered inventory designed to measure the intensity of depressive symptoms (Beck, Steer, & Brown, 1996). Scores ranging between 0 and 13 are indicative of minimal depression; scores that fall between 14 and 19 are considered to reflect a mild level of depression; scores of 20 to 28 are considered moderate; and a score ranging from 29 to 63 is labeled severe. | Baseline, 12 and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cortisol, metyrapone, hypercortisolism, mild hypercortisolism