Clinical trial NCT02364089: Surgery of Subclinical Cortisol Secreting Adrenal Incidentalomas
Official title: Surgery of Subclinical Cortisol Secreting Adrenal Incidentalomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Adrenal Incidentalomas
Keywords: Adrenal Incidentaloma
Subclinical Cushing's syndrome
Hypertension
Cardiovascular Risk Factors
Metabolic Syndrome
Surgery of adrenal tumor
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
First posted: 2015-02-16
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Blood pressure value and SAHR step 12 months after inclusion
timeFrame: 13 months
Secondary outcomes:
measure: Antihypertensive treatment score and daily drug dose
timeFrame: 12 months
measure: Incidence of complications in the two strategies.
timeFrame: 12 months
measure: Direct costs of the two strategies.
timeFrame: 12 months
measure: Assessment of predictive factors for the success of surgery on BP
timeFrame: 12 months
measure: number of patients requiring antihypertensive treatment
timeFrame: 12 months
measure: 24 hours ambulatory blood pressure monitoring values
timeFrame: At inclusion (day 0) and at 12 months
measure: Blood glucose and lipid lowering agents values
timeFrame: 12 months
measure: Cardiovascular risk factors/markers level
timeFrame: 12 months
measure: Number of patients with persistent diabetes, dyslipidemia and metabolic syndrome
timeFrame: 12 months
measure: Evaluation of quality of life
timeFrame: At inclusion and 12 months
Other outcomes:
Locations:
city: Strasbourg
country: France
facility: Service de Médecine Interne, Endocrinologie et Nutrition - CHU de Strasbourg
state: Alsace
city: Pessac
country: France
facility: Service Endocrinologie, Diabétologie, maladies métaboliques - CHU de Bordeaux
state: Aquitaine
city: Caen
country: France
facility: Service d'Endocrinologie - Niveau 18 - Caen CHU Côte de Nacre
state: Basse-Normandie
city: Amiens
country: France
facility: Service d'Endocrinologie, Diabétologie, Nutrition - CHU d'Amiens
state: Haut De France
city: Rouen
country: France
facility: Endocrinologie, Diabète et Maladies Métaboliques - CHU de Rouen
state: Haute-Normandie
city: Le Kremlin Bicêtre
country: France
facility: Service d'Endocrinologie et des Maladies de la Reproduction- Assistance Publique - Hôpitaux de Paris - Hôpial Bicêtre
state: ILE DE France
city: Paris
country: France
facility: Assistance Publique - Hôpitaux de Paris - Hôpital COCHIN
state: ILE DE France
city: Paris
country: France
facility: Service d'Hypertension et de Médecine Vasculaire - Assistance Publique - Hôpitaux de Paris - Hôpital européen Georges Pompidou
state: ILE DE France
city: Toulouse
country: France
facility: Service d'Endocrinologie et Maladies Métabolique - CHU de Toulouse
state: Midi-Pyrénées
city: Lille
country: France
facility: Service d'Endocrinologie, Diabétologie et Métabolisme - CHRU de LILLE
state: Nord-Pas-de-Calais
city: Angers
country: France
facility: Département Endocrinologie-Diabétologie -Nutrition - CHU d'ANGERS
state: Pays De La Loire
city: Nantes
country: France
facility: CIC Endocrinologie-Nutrition - CHU de Nantes
state: Pays De La Loire
city: Marseille
country: France
facility: Service d'Endocrinologie, Diabète et Maladies Métaboliques - Assistance publique - Hôpitaux de Marseille
state: Provence-Alpes-Côte d'Azur
city: Poitiers
country: France
facility: CHU de Poitiers
city: Berlin
country: Germany
facility: Endokrinologie, Diabetes und Ernährungsmedizin, Campus Mitte, Medizinische Klinik - Charité - Universitätsmedizin Berlin
city: Würzburg
country: Germany
facility: Department of Internal Medicine I, Endocrine and Diabetes Uni -University Hospital Würzburg
city: Bologna
country: Italy
facility: S Orsola-Malpighi Hospital
Study officials:
affiliation: University Hospital, Bordeaux
name: Eric FRISON, Dr
role: STUDY_CHAIR
References: