Surgery of Subclinical Cortisol Secreting Adrenal Incidentalomas

NCT ID: NCT02364089

Last Updated: 2023-07-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-09
• Study Completion Date: 2022-11-23

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.

Conditions

Adrenal Incidentalomas

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Surgery followed by intensive medical care

Laparoscopic surgical removal of the adrenal tumor

Group Type: EXPERIMENTAL

Laparoscopic surgical removal of the adrenal tumor

Intervention Type: PROCEDURE

Intensive medical treatment only

Standardized medical treatment of hypertension by SAHR.

Group Type: ACTIVE_COMPARATOR

Standardized medical treatment of hypertension by SAHR

Intervention Type: DRUG

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.

Interventions

Laparoscopic surgical removal of the adrenal tumor

Intervention Type: PROCEDURE

Standardized medical treatment of hypertension by SAHR

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.

Intervention Type: DRUG

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.

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Bordeaux

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eric FRISON, Dr

Role: STUDY_CHAIR

University Hospital, Bordeaux

Locations

Service de Médecine Interne, Endocrinologie et Nutrition - CHU de Strasbourg

Strasbourg, Alsace, France

Service Endocrinologie, Diabétologie, maladies métaboliques - CHU de Bordeaux

Pessac, Aquitaine, France

Service d'Endocrinologie - Niveau 18 - Caen CHU Côte de Nacre

Caen, Basse-Normandie, France

Service d'Endocrinologie, Diabétologie, Nutrition - CHU d'Amiens

Amiens, Haut de France, France

Endocrinologie, Diabète et Maladies Métaboliques - CHU de Rouen

Rouen, Haute-Normandie, France

Service d'Endocrinologie, Diabétologie et Métabolisme - CHRU de LILLE

Lille, Hauts-de-France, France

Service d'Endocrinologie et Maladies Métabolique - CHU de Toulouse

Toulouse, Midi-Pyrénées, France

Département Endocrinologie-Diabétologie -Nutrition - CHU d'ANGERS

Angers, Pays de la Loire Region, France

CIC Endocrinologie-Nutrition - CHU de Nantes

Nantes, Pays de la Loire Region, France

Service d'Endocrinologie, Diabète et Maladies Métaboliques - Assistance publique - Hôpitaux de Marseille

Marseille, Provence-Alpes-Côte d'Azur Region, France

CHU de Poitiers

Poitiers, , France

Service d'Endocrinologie et des Maladies de la Reproduction- Assistance Publique - Hôpitaux de Paris - Hôpial Bicêtre

Le Kremlin-Bicêtre, Île-de-France Region, France

Assistance Publique - Hôpitaux de Paris - Hôpital COCHIN

Paris, Île-de-France Region, France

Service d'Hypertension et de Médecine Vasculaire - Assistance Publique - Hôpitaux de Paris - Hôpital européen Georges Pompidou

Paris, Île-de-France Region, France

Endokrinologie, Diabetes und Ernährungsmedizin, Campus Mitte, Medizinische Klinik - Charité - Universitätsmedizin Berlin

Berlin, , Germany

Department of Internal Medicine I, Endocrine and Diabetes Uni -University Hospital Würzburg

Würzburg, , Germany

S Orsola-Malpighi Hospital

Bologna, , Italy

Countries

France; Germany; Italy

References

Tabarin A, Espiard S, Deutschbein T, Amar L, Vezzossi D, Di Dalmazi G, Reznik Y, Young J, Desailloud R, Goichot B, Drui D, Assie G, Lefebvre H, Mai K, Castinetti F, Laboureau S, Terzolo M, Ferriere A, Georget A, Frison E, Vantyghem MC, Fassnacht M, Gosse P; CHIRACIC Collaborators. Surgery for the treatment of arterial hypertension in patients with unilateral adrenal incidentalomas and mild autonomous cortisol secretion (CHIRACIC): a multicentre, open-label, superiority randomised controlled trial. Lancet Diabetes Endocrinol. 2025 Jul;13(7):580-590. doi: 10.1016/S2213-8587(25)00062-2. Epub 2025 May 12.

Reference Type: DERIVED

PMID: 40373786 (View on PubMed)

Other Identifiers

CHUBX 2012/34

Identifier Type: -

Identifier Source: org_study_id