Surgery of Subclinical Cortisol Secreting Adrenal Incidentalomas

Study Overview
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Brief Summary
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The general objective is to evaluate the consequences of surgical removal of SCSI on hypertension and cardiovascular risk factors in order to determine on an evidence-based basis if surgical excision of SCSI is preferable to an intensive medical regimen in patients with hypertension.

Detailed Description
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Adrenal incidentalomas are unsuspected adrenal masses found during abdominal imaging. With the widespread use of computed tomography and MRI, adrenal incidentalomas are found in approximately 2% of patients. In an endocrinology setting, the majority of these masses are benign adenomas of the adrenal cortex. Approximately 10% of these adenomas display little excess of cortisol secretion associated to some degree of secretory autonomy but that are insufficient to generate overt Cushing's syndrome (Subclinical Secreting Cortisol incidentalomas or SCSI). However, hypertension and to a lesser degree obesity and impaired glucose tolerance are very frequent amongst patients with SCSI. The hypothesis that the mild hypercortisolism associated with SCSI is responsible for these clinical consequences is substantiated by few studies describing improvement after resection of SCSI. However, these studies were retrospective, uncontrolled and suffered from imprecision and numerous methodological bias. Thus, whether surgery is more beneficial than medical treatment is currently unknown and there is no consensus on the appropriate treatment for SCSI. Patient selection Run-In period. Discontinuation of previous antihypertensive treatments and prescription of a standardized anti-hypertensive drug regimen (SAHR). Monthly Blood Pressure (BP) measurement using home BP monitoring. The duration of the Run-In periods will be ≤ 6 months and will end when BP will be controlled with the SAHR at two consecutive visits. End of RI Second endocrine assessment for eligibility Randomization (Ra): 24h Ambulatory BP measurement, anthropometric and metabolic evaluation. Quality of life and cognition questionnaires. Randomization in 2 groups : Gr 1 Treatment group : Surgery followed by intensive medical care ; Gr 2 : Control Group : intensive medical care only. Ra + 1Mo: Surgery in Group 1 Ra + 2.5 Mo to Ra + 13 Mo: 6 weeks interval follow-up Evaluation of home BP monitoring and adaptation of the SAHR. A step by step reduction of the SAHR will be attempted in the two patient groups at Ra+2.5Mo. A second attempt will systematically be performed in both groups at Ra+8.5 Medical evaluation of associated metabolic conditions (obesity, diabetes, dyslipidemia) and adaptation of treatments Record of medical events and side effects of treatments Ra + 13Mo: Final evaluation. Endocrine assessment. 24h Ambulatory BP measurement, anthropometric and metabolic evaluation. Quality of life and cognition questionnaires.

Official Title
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Surgery of Subclinical Cortisol Secreting Adrenal Incidentalomas

Conditions
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Adrenal Incidentalomas

Intervention / Treatment
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* Procedure: Laparoscopic surgical removal of the adrenal tumor
* Drug: Standardized medical treatment of hypertension by SAHR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≤ 80 years. Unilateral SCSI: Incidentally discovered adrenal tumor with attenuation < 20 UH and/or relative wash-out (> 40%) or absolute wash-out (> 60%) of contrast media and size ≥ 2 cm. Tumors that do not fulfil these criteria might be included if their size is ≤ 4 cm, do not exhibit signs of malignancy (necrosis areas, large and irregular rims) and are stable in size after ≥ 6 months of follow-up. Impaired 1 mg dexamethasone suppression (Cortisol > 138 nmol/L or 5 µg/dL), OR Impaired 1 mg dexamethasone suppression (Cortisol > 50 nmol/L or 1.8 µg/dL) AND one biochemical abnormalities among: 08h00 plasma ACTH < 2.2 pmol/L or plasma ACTH following CRH injection ≤ 6.6 pmol/L, midnight plasma cortisol > 150 nmol/L, increased late evening salivary cortisol, UFC between 1 and 2.0 x N. Treated BP (and confirmed using an automated home BP monitoring) OR increased BP (≥ 135/85 mmHg) none treated, using an automated home BP monitoring. Exclusion Criteria: Age > 80 y, Bilateral SCSI, Warning: Contralateral nodular formations < 10 mm are considered as negligible, Incidentally discovered adrenal tumor size < 2 cm, Malignant hypertension, stroke, pulmonary oedema or myocardial infarction during the previous year, Malignant hypertension during the Run-in period, Obligatory beta blocker treatment. Patients receiving betablocker treatment for other purpose than hypertension can be included. However, to be included, patients should need at least an extrastep of hypertensive treatment in order to allow the SAHR decrease following randomisation. The dose of betablocker has to stay the same during all the study. UFC > ULN x 2.0 N, 8h00 plasma ACTH > 20 pg/ml (4.4 pmol/L), Chronic renal insufficiency (clearance < 30 mL/min) Dissipation of the biological endocrine criteria for SCSI at the end of the Run-In period, Intake of exogenous corticoids or drugs that interfere with dexamethasone metabolism, Pregnancy, Childbearing woman with no contraceptive effective method (HAS criteria - 77), Adverse pathological conditions responsible for reduced life expectancy. Exclusion criteria after the Run-In period: Spontaneous resolution of biological features of SCSI Hypertension not confirmed with standard blood pressure self-measurement device Hypertension not controlled (≥ 135/85 mmHg) at the end of the Run-In period Malignant hypertension (> 175/115 mmHg) Patient receiving betablocker and not receiving at least an extrastep of hypertensive treatment of the SAHR

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Surgery followed by intensive medical care<br>Laparoscopic surgical removal of the adrenal tumor | Procedure: Laparoscopic surgical removal of the adrenal tumor<br> <br> |
| Active Comparator: Intensive medical treatment only<br>Standardized medical treatment of hypertension by SAHR. | Drug: Standardized medical treatment of hypertension by SAHR<br>* Standardized anti-hypertensive drug regimen has been established according to international recommendations and includes the following steps: step 1: Angiotensin converting enzyme inhibitor (ACE-I) or angiotensin II receptor antagonist (ARBs) at half-dose (Ranipril 5mg or Ibesartan 150 mg ) step 2: CEI or ARA2 at full dose (Ranipril 10 mg or Ibesartan 300 mg) step 3: Add-on of Amlodipine 10 mg or Diltiazem LP 300 mg step 4: Add-on of Indapamide LP 1.5 mg step 5: Add-on of Spironolactone 25 mg step 6: Add-on of Bisoprolol 10 mg step 7: Add-on of Prazosine LP 5mg/day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure value and SAHR step 12 months after inclusion | Treatment response will defined as a reduction of at least 1 step of SAHR at the end of the study, with BP maintained within the study objectives (<135 mm Hg systolic and <85 mm Hg diastolic) according to self-measurement at home. | 13 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antihypertensive treatment score and daily drug dose |  | 12 months | 
| Incidence of complications in the two strategies. |  | 12 months | 
| Direct costs of the two strategies. |  | 12 months | 
| Assessment of predictive factors for the success of surgery on BP | age, family history of hypertension, duration of hypertension, kidney function, biochemical endocrine abnormalities, urinary steroid profile | 12 months | 
| number of patients requiring antihypertensive treatment |  | 12 months | 
| 24 hours ambulatory blood pressure monitoring values |  | At inclusion (day 0) and at 12 months | 
| Blood glucose and lipid lowering agents values |  | 12 months | 
| Cardiovascular risk factors/markers level | Comparison of the two therapeutic strategies with regard to cardiovascular risk factors/markers: BMI, body composition evaluated by DEXA, abdominal fat evaluated on CT-scan, fasting blood glucose and insulin, HbA1C, HOMA-IR (homeostasis model of assessment of insulin resistance) and OGTT (oral glucose tolerance test), blood lipids, pro-inflammatory adipokines | 12 months | 
| Number of patients with persistent diabetes, dyslipidemia and metabolic syndrome |  | 12 months | 
| Evaluation of quality of life | Comparison of the two therapeutic strategies with regard to quality of life | At inclusion and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adrenal Incidentaloma, Subclinical Cushing's syndrome, Hypertension, Cardiovascular Risk Factors, Metabolic Syndrome, Surgery of adrenal tumor