Adrenal IncidentalomaNCT04860180
Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas
A study testing adrenalectomy in people with Adrenal Incidentaloma and Subclinical Hypercortisolism, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico.
Trial summary
Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, frequently found in patients with adrenal adenomas (estimated prevalence: 0.8-2% after 60 years of age). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Adrenal Incidentaloma, Subclinical Hypercortisolism
- What is being tested?
- adrenalectomy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 61 participants
- Where
- No sites listed yet
- Study dates
- 29 Sep 2016to 8 Dec 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- unilateral adrenal incidentaloma larger than 1 cm
- cortisol after 1-mg overnight dexamethasone suppression test (1mgDST) between 1.8 and 5 mcg/dl
Who cannot join
- hypogonadism, thyrotoxicosis, chronic renal failure and hepatic disease, alcoholism, eating, rheumatologic or hematological disorders;
- intake of drugs influencing cortisol and dexamethasone metabolism or cortisol secretion;
- signs of hypercortisolism (moon facies, striae rubrae, easy bruising);
- possible metastatic disease or radiologic features not consistent with adrenocortical adenoma at computed tomography (CT);
- pheochromocytoma and aldosteronoma;
- non-adrenal SH.
About this study
Official title: Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas on Cardiovascular, Metabolic, Neuropsychological and Bone Manifestations: Respective Roles of Cortisol Secretion and Glucocorticoid Sensitivity
Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, frequently found in patients with adrenal adenomas (estimated prevalence: 0.8-2% after 60 years of age). Although SH may lead to diabetes, hypertension and osteoporosis, the diagnostic SH criteria and those suggesting the need of adrenalectomy are debated. Indeed, beside the cortisol secretion, the individual cortisol sensitivity may play a role in determining the SH consequences.
Subjects with possible SH due to adrenal adenoma will be randomized to surgery/conservative follow up. The effects of surgery on the cardiovascular, bone, metabolic complications of SH and on neuropsychological aspects and quality of life (QoL) and the possibility to predict them by using cortisol sensitivity and secretion markers will be studied. The study may clarify how to individuate patients who can benefit from surgery. These results will help reducing the costs of both useless surgical operations and SH consequences.
Read the detailed description
Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, which is present in up to the 30% of patients with incidentally discovered adrenal adenomas (adrenal incidentalomas, AI). Since AI are present in 7-10% of individuals after 60 years of age, the estimated SH prevalence in this population is 0.8-2%. In patients with SH due to an adrenal adenoma the risk of diabetes, hypertension, cardiovascular events, osteoporosis and mortality seems to be increased, and monolateral adrenalectomy beneficial. However, no randomized studies evaluated the effects of surgery on SH consequences and established the criteria indicating the need of surgery itself. Thus, in many patients the SH diagnosis is uncertain and the best approach (surgical or conservative) unknown. These uncertainties are also due to the influence of the individual glucocorticoid (GC) sensitivity. Indeed, in the single individual the various polymorphisms of GC receptor (GR) and the different 11ß-hydroxysteroid-dehydrogenase type 2 enzyme (11HSD2) activity, regulating the tissue exposure to the active GC, may differently predispose to the consequences of GC excess. Therefore, in AI patients, beside the evaluation of the degree of the cortisol hypersecretion, the assessment of the cortisol sensitivity may be useful in establishing the individual risk of SH consequences and the possible usefulness of a surgical approach.
Specific Aim:
In AI subjects with uncertain SH the combined evaluation of the clinical features together with the parameters of cortisol secretion and sensitivity will consent to decide which patient has the greatest probability to ameliorate after surgery.
- To assess the variation of blood pressure control, lipids and glucose metabolism, vascular damage, bone mineral density (BMD), clinical and morphometric vertebral fractures, body composition, coagulation parameters, neuropsychological aspects and quality of life (QoL) in AI patients with uncertain SH after the surgical removal of the adrenal mass or after a conservative treatment.
- To assess in AI patients and uncertain hypercortisolism the effect of the surgical and conservative approach on cardiovascular, metabolic and bone manifestations, neuropsychological aspects and quality of life (QoL), in relation to the degree of cortisol secretion and sensitivity.
- To establish the best clinical-biochemical criteria for diagnosing SH, on the basis of the changes of the outcomes after the surgical or conservative approach, and therefore, for addressing the treatment of choice in the individual patient with AI.
Methods. During the enrollment period (24 months), all patients between 40 and 75 years of age referred for unilateral AI larger than 1 cm will be evaluated.
In all subjects, adrenocorticotroph hormone (ACTH), urinary free cortisol (UFC), cortisol after 1-mg overnight dexamethasone suppression test (1mgDST) and the GR polymorphisms of N363S, BclI and ER22/23EK will be assessed. Patients with 1mgDST >1.8 mcg/dL will undergo a low dose (2 mg for 2 days) dexamethasone suppression test (LDDST). Patients with 1mgDST and LDDST >5 mcg/dL and suppressed (<5 pg/mL) ACTH levels will be excluded as affected by biochemically overt hypercortisolism, that requires surgery. AI patients with 1mgDST or LDDST <1.8 mcg/dL will be excluded as certainly not affected with SH. AI patients with AI >5 cm will leave the study as in this case surgery is mandatory.
Eventually, after the enrollment period, 54 AI patients with uncertain SH will be included and randomized to surgery (Group1) or conservative treatment (Group 2). The follow-up period will last 24 months (after withdrawal of GC substitution therapy, if needed, for Group 1). Group 1 patients will undergo laparoscopic or laparotomic adrenalectomy, depending on the AI size and their clinical characteristics.
Evaluations at baseline, 6, 12 and 24 months: blood pressure (BP), body weight (BW), body mass index (BMI), waist circumference, glucose, lipid and coagulation parameters, body composition and adenoma size by CT (Group 2 patients).
Group 2 patients with a >1 cm adenoma increase or appearance of overt SH will leave the study. At baseline and after 24 months, bone mineral density (BMD) and quality (by trabecular bone score, TBS), vertebral fractures (VFx), carotid atherosclerosis, neuropsychological aspects and QoL, will be assessed.
The patients will be defined: i) obese, in the presence of BMI >30 kg/m2; ii) hypertensive in the presence of systolic BP >130 mmHg and/or diastolic BP >85 mmHg and/or any antihypertensive treatment; iii) diabetic, in the presence of the World Health Organization criteria, and/or any hypoglycemic drug, iv) dyslipidemic, in the presence of triglyceride levels >150 mg/dl or high-density lipoprotein (HDL) cholesterol levels <40 or 50 mg/dl in males and females, respectively.
The improvement/worsening during follow-up will be defined as follows: for obesity in the presence of a >5% BW decrease/increase, for hypertension if the non-hypertensive patients passed from a pre-hypertension category to another or the hypertensive patients from a hypertension grade to another; for diabetes and dyslipidemia if fasting glucose and cholesterol levels pass from a category to another, respectively, following the Adult Treatment Panel III criteria.
The efficacy of the surgical and conservative approach on the basis of the changes of BP, BW, glucose and lipid control, BMD, VFx incidence (primary outcomes) will be compared. The effect of surgery on the coagulation parameters, carotid atherosclerosis, body composition, neuropsychological aspects and QoL (secondary outcomes) will be also evaluated.
At baseline, and at 6, 12 and 24 months, beside ACTH, 1mgDST and UFC, the midnight salivary cortisol (MSalC) and urinary free cortisone (UFCo) levels and the UFC/UFCo ratio (index of 11HSD2 activity) will be assessed In Group 1 and Group 2 patients the association between the changes of the primary and secondary outcomes with the cortisol secretion parameters and the presence/absence of GC sensitizing GR polymorphisms and the degree of 11HSD2 activity, will be evaluated.
An algorithm for predicting the effect of the surgical or conservative approach on the primary outcomes in the individual AI patient with uncertain SH. The algorithm, based on the combination of the SH complications at baseline (hypertension, osteoporotic fractures, diabetes) with the presence/absence of GC sensitizing GR polymorphisms, degree of 11HSD2 activity and parameters of cortisol secretion, will be retrospectively tested on the study population, will be elaborated. This would consent to evaluate positive and negative predictive value of the algorithm for predicting the response to surgery in the individual patient with AI.
- Being tested
- adrenalectomy
- Medical subject headings
- Adrenal incidentaloma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
adrenalectomyProcedure or surgery
| Study group | Role | What they receive |
|---|---|---|
| A, surgery | Experimental | adrenalectomy Receives: Procedure: adrenalectomy |
| B, observation | No intervention | conservative follow up |
What is being measured
The primary outcome is the main question the study is designed to answer.
variation of blood pressure
To assess the variation of blood pressure ambulatory systolic and diastolic blood pressure (BP, mmHg), and antihypertensive treatment at baseline and follow-up will be assessed; BP will be considered improved or worsened if the non-hypertensive patients passed from a pre-hypertension category to another or the hypertensive patients from a hypertension grade to another in accordance to giudelines, of if if antihypertensive treatment was reduced by 50%
Measured: 6 months
variation of glucose levels
To assess the variation of glucose levels, fasting glucose levels and glucose levels after oral glucose tolerance test will be evaluated at baseline and follow-up. Glucose levels will be considered improved or worsened if fasting glucose levels pass from a category to another, following the Adult Treatment Panel III criteria or if antidiabetic treatment was reduced by 50%
Measured: 6 months
variation of lipids
At baseline and follow up triglyceride levels; total cholesterol levels, HDL and LDL levels (mg/dl) will be evaluated. Dyslipidemia will be diagnosed in the presence of triglyceride levels >150 mg/dl or high-density lipoprotein (HDL) cholesterol levels <40 or 50 mg/dl in males and females. dyslipidemia will be defined improved or worsened if cholesterol levels pass from a category to another, following the Adult Treatment Panel III criteria
Measured: 6 months
variation of body weight
At baseline and follow up body weight (kilograms) will be evaluated. the improvement/worsening during follow-up will be defined in the presence of a >5% BW decrease/increase
Measured: 6 months
variation of bone mineral density (BMD)
To assess the variation of bone mineral density at baseline and follow-up a Dual-energy X-ray absorptiometry (DXA) scan will be performed
Measured: 24 months
occurrence of vertebral fractures
A dorso-lumbar spine x-ray to evaluate the presence of morphometric fractures (presence/absence) will be performed
Measured: 24 months
variation of intimal medial thickness
To assess the variation of vascular damage a supra-aortic trunk echo-Doppler to evaluate at baseline and follow-up variations of intimal medial thickness will be performed
Measured: 12 months
variation of Relative wall thickness (RWT)
the variation of Relative wall thickness (RWT) will be evaluated by an echocardiography. It will be calculated from Left ventricular end diastolic dimension (LVEDD) (mm); Interventricular septal end diastole (IV Sd, mm) and Posterior wall thickness at end-diastole (PWd) parameters (mm)
Measured: 12 months
variation of Sheehan Disability Scale
Sheehan Disability Scale will be evaluated to assess perceived stress (SDS-stress scale ranges 1-10, a higher score means higher levels of stress)
Measured: 6 months
Cognitive evaluation by Brief Assessment Cognition in Schizophrenia (BACS) score
BACS evaluate verbal memory score (normal if >33); working memory (normal if >14.9); verbal fluency (normal if >31.6), symbol coding (normal if >40.5), tower of london (>12.4)
Measured: 6 months
Secondary outcomes (2)
cortisol secretion and sensitivity
To correlate the effect of the surgical and conservative approach in relation to the degree of cortisol secretion and sensitivity we will evaluate the GR polymorphisms of N363S, BclI and ER22/23EK ,midnight salivary cortisol (MSalC) and urinary free cortisone (UFCo) levels and the UFC/UFCo ratio (index of 11HSD2 activity)
Measured: 24 months
variation of Inflammation markers and bone metabolism markers
irisine, Tumor Necrosing Factor (TNF)- alpha, interleukin (IL)-6, adiponectin, resistin, sclerostin, Dickkopf-related protein (DKK) 1, N-terminal propeptide of type 1 collagen (P1NP) , monocytechemoattractant protein 1 (CCL2/MCP-1) levels will be assessed (pg/ml). Paired samples T-test will be used to compare baseline and follow-up levels.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Apr 2021
- Study start29 Sep 2016
- Primary completion22 Feb 2021
- Study completion8 Dec 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (18)Papers the sponsor has linked to this study.
- Other trials for Adrenal IncidentalomaStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 61 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Casa Sollievo della Sofferenza IRCCS, I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio, Ministry of Health, Italy
- Responsible party
- Principal investigator, Iacopo Chiodini, Istituto Auxologico Italiano
- Investigators
- Iacopo Chiodini, Professor, Principal investigator, Istituto Auxologico Italiano
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04860180
- Sponsor's protocol ID
- RF-2013-02356606
- Status last verified
- Apr 2021
- First submitted
- 16 Feb 2021
- Last updated
- 26 Apr 2021
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Reincke M. Subclinical Cushing's syndrome. Endocrinol Metab Clin North Am. 2000 Mar;29(1):43-56. doi: 10.1016/s0889-8529(05)70115-8.
PubMed 10732263Terzolo M, Bovio S, Reimondo G, Pia A, Osella G, Borretta G, Angeli A. Subclinical Cushing's syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am. 2005 Jun;34(2):423-39, x. doi: 10.1016/j.ecl.2005.01.008.
PubMed 15850851Chiodini I, Morelli V, Masserini B, Salcuni AS, Eller-Vainicher C, Viti R, Coletti F, Guglielmi G, Battista C, Carnevale V, Iorio L, Beck-Peccoz P, Arosio M, Ambrosi B, Scillitani A. Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian multicenter study. J Clin Endocrinol Metab. 2009 Sep;94(9):3207-14. doi: 10.1210/jc.2009-0468. Epub 2009 Jun 23.
PubMed 19549741Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, Salcuni AS, Dolci A, Mendola M, Arosio M, Ambrosi B, Scillitani A, Ghigo E, Beck-Peccoz P, Terzolo M, Chiodini I. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab. 2014 Mar;99(3):827-34. doi: 10.1210/jc.2013-3527. Epub 2014 Jan 1.
PubMed 24423350Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E, Mosconi C, Golfieri R, Paccapelo A, Pagotto U, Pasquali R. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol. 2014 May;2(5):396-405. doi: 10.1016/S2213-8587(13)70211-0. Epub 2014 Jan 29.
PubMed 24795253Manenschijn L, van den Akker EL, Lamberts SW, van Rossum EF. Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Ann N Y Acad Sci. 2009 Oct;1179:179-98. doi: 10.1111/j.1749-6632.2009.05013.x.
PubMed 19906240Szappanos A, Patocs A, Toke J, Boyle B, Sereg M, Majnik J, Borgulya G, Varga I, Liko I, Racz K, Toth M. BclI polymorphism of the glucocorticoid receptor gene is associated with decreased bone mineral density in patients with endogenous hypercortisolism. Clin Endocrinol (Oxf). 2009 Nov;71(5):636-43. doi: 10.1111/j.1365-2265.2009.03528.x. Epub 2009 Jan 22.
PubMed 19207316Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004 Oct;25(5):831-66. doi: 10.1210/er.2003-0031.
PubMed 15466942Eller-Vainicher C, Morelli V, Ulivieri FM, Palmieri S, Zhukouskaya VV, Cairoli E, Pino R, Naccarato A, Scillitani A, Beck-Peccoz P, Chiodini I. Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism. J Bone Miner Res. 2012 Oct;27(10):2223-30. doi: 10.1002/jbmr.1648.
PubMed 22549969Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, Pivonello R, Stalla G, Lamberts SW, Glusman JE. Evaluation of health-related quality of life in patients with Cushing's syndrome with a new questionnaire. Eur J Endocrinol. 2008 May;158(5):623-30. doi: 10.1530/EJE-07-0762.
PubMed 18426820Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003 Jan;26 Suppl 1:S5-20. doi: 10.2337/diacare.26.2007.s5. No abstract available.
PubMed 12502614Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97. doi: 10.1001/jama.285.19.2486. No abstract available.
PubMed 11368702Vidal J. Updated review on the benefits of weight loss. Int J Obes Relat Metab Disord. 2002 Dec;26 Suppl 4:S25-8. doi: 10.1038/sj.ijo.0802215.
PubMed 12457296Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O'Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007 Jun;25(6):1105-87. doi: 10.1097/HJH.0b013e3281fc975a. No abstract available.
PubMed 17563527Athimulam S, Delivanis D, Thomas M, Young WF, Khosla S, Drake MT, Bancos I. The Impact of Mild Autonomous Cortisol Secretion on Bone Turnover Markers. J Clin Endocrinol Metab. 2020 May 1;105(5):1469-77. doi: 10.1210/clinem/dgaa120.
PubMed 32154561
Study at a glance
From the registry record, last updated by the sponsor on 26 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas on Cardiovascular, Metabolic, Neuropsychological and Bone Manifestations: Respective Roles of Cortisol Secretion and Glucocorticoid Sensitivity
- ClinicalTrials.gov ID
- NCT04860180
- Acronym / sponsor ID
- RF-2013-02356606
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 61 participants (estimated)
- Lead sponsor
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoUniversity, hospital or other
- Collaborators
- Casa Sollievo della Sofferenza IRCCS, I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio, Ministry of Health, Italy
- Study start
- 29 Sep 2016 (actual)
- Primary completion
- 22 Feb 2021 (actual)
- Study completion
- 8 Dec 2022 (estimated)
- First posted
- 26 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, frequently found in patients with adrenal adenomas (estimated prevalence: 0.8-2% after 60 years of age). Although SH may lead to diabetes, hypertension and osteoporosis, the diagnostic SH criteria and those suggesting the need of adrenalectomy are debated. Indeed, beside the cortisol secretion, the individual cortisol sensitivity may play a role in determining the SH consequences.
Subjects with possible SH due to adrenal adenoma will be randomized to surgery/conservative follow up. The effects of surgery on the cardiovascular, bone, metabolic complications of SH and on neuropsychological aspects and quality of life (QoL) and the possibility to predict them by using cortisol sensitivity and secretion markers will be studied. The study may clarify how to individuate patients who can benefit from surgery. These results will help reducing the costs of both useless surgical operations and SH consequences.
Detailed description
Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, which is present in up to the 30% of patients with incidentally discovered adrenal adenomas (adrenal incidentalomas, AI). Since AI are present in 7-10% of individuals after 60 years of age, the estimated SH prevalence in this population is 0.8-2%. In patients with SH due to an adrenal adenoma the risk of diabetes, hypertension, cardiovascular events, osteoporosis and mortality seems to be increased, and monolateral adrenalectomy beneficial. However, no randomized studies evaluated the effects of surgery on SH consequences and established the criteria indicating the need of surgery itself. Thus, in many patients the SH diagnosis is uncertain and the best approach (surgical or conservative) unknown. These uncertainties are also due to the influence of the individual glucocorticoid (GC) sensitivity. Indeed, in the single individual the various polymorphisms of GC receptor (GR) and the different 11ß-hydroxysteroid-dehydrogenase type 2 enzyme (11HSD2) activity, regulating the tissue exposure to the active GC, may differently predispose to the consequences of GC excess. Therefore, in AI patients, beside the evaluation of the degree of the cortisol hypersecretion, the assessment of the cortisol sensitivity may be useful in establishing the individual risk of SH consequences and the possible usefulness of a surgical approach.
Specific Aim:
In AI subjects with uncertain SH the combined evaluation of the clinical features together with the parameters of cortisol secretion and sensitivity will consent to decide which patient has the greatest probability to ameliorate after surgery.
- To assess the variation of blood pressure control, lipids and glucose metabolism, vascular damage, bone mineral density (BMD), clinical and morphometric vertebral fractures, body composition, coagulation parameters, neuropsychological aspects and quality of life (QoL) in AI patients with uncertain SH after the surgical removal of the adrenal mass or after a conservative treatment.
- To assess in AI patients and uncertain hypercortisolism the effect of the surgical and conservative approach on cardiovascular, metabolic and bone manifestations, neuropsychological aspects and quality of life (QoL), in relation to the degree of cortisol secretion and sensitivity.
- To establish the best clinical-biochemical criteria for diagnosing SH, on the basis of the changes of the outcomes after the surgical or conservative approach, and therefore, for addressing the treatment of choice in the individual patient with AI.
Methods. During the enrollment period (24 months), all patients between 40 and 75 years of age referred for unilateral AI larger than 1 cm will be evaluated.
In all subjects, adrenocorticotroph hormone (ACTH), urinary free cortisol (UFC), cortisol after 1-mg overnight dexamethasone suppression test (1mgDST) and the GR polymorphisms of N363S, BclI and ER22/23EK will be assessed. Patients with 1mgDST >1.8 mcg/dL will undergo a low dose (2 mg for 2 days) dexamethasone suppression test (LDDST). Patients with 1mgDST and LDDST >5 mcg/dL and suppressed (<5 pg/mL) ACTH levels will be excluded as affected by biochemically overt hypercortisolism, that requires surgery. AI patients with 1mgDST or LDDST <1.8 mcg/dL will be excluded as certainly not affected with SH. AI patients with AI >5 cm will leave the study as in this case surgery is mandatory.
Eventually, after the enrollment period, 54 AI patients with uncertain SH will be included and randomized to surgery (Group1) or conservative treatment (Group 2). The follow-up period will last 24 months (after withdrawal of GC substitution therapy, if needed, for Group 1). Group 1 patients will undergo laparoscopic or laparotomic adrenalectomy, depending on the AI size and their clinical characteristics.
Evaluations at baseline, 6, 12 and 24 months: blood pressure (BP), body weight (BW), body mass index (BMI), waist circumference, glucose, lipid and coagulation parameters, body composition and adenoma size by CT (Group 2 patients).
Group 2 patients with a >1 cm adenoma increase or appearance of overt SH will leave the study. At baseline and after 24 months, bone mineral density (BMD) and quality (by trabecular bone score, TBS), vertebral fractures (VFx), carotid atherosclerosis, neuropsychological aspects and QoL, will be assessed.
The patients will be defined: i) obese, in the presence of BMI >30 kg/m2; ii) hypertensive in the presence of systolic BP >130 mmHg and/or diastolic BP >85 mmHg and/or any antihypertensive treatment; iii) diabetic, in the presence of the World Health Organization criteria, and/or any hypoglycemic drug, iv) dyslipidemic, in the presence of triglyceride levels >150 mg/dl or high-density lipoprotein (HDL) cholesterol levels <40 or 50 mg/dl in males and females, respectively.
The improvement/worsening during follow-up will be defined as follows: for obesity in the presence of a >5% BW decrease/increase, for hypertension if the non-hypertensive patients passed from a pre-hypertension category to another or the hypertensive patients from a hypertension grade to another; for diabetes and dyslipidemia if fasting glucose and cholesterol levels pass from a category to another, respectively, following the Adult Treatment Panel III criteria.
The efficacy of the surgical and conservative approach on the basis of the changes of BP, BW, glucose and lipid control, BMD, VFx incidence (primary outcomes) will be compared. The effect of surgery on the coagulation parameters, carotid atherosclerosis, body composition, neuropsychological aspects and QoL (secondary outcomes) will be also evaluated.
At baseline, and at 6, 12 and 24 months, beside ACTH, 1mgDST and UFC, the midnight salivary cortisol (MSalC) and urinary free cortisone (UFCo) levels and the UFC/UFCo ratio (index of 11HSD2 activity) will be assessed In Group 1 and Group 2 patients the association between the changes of the primary and secondary outcomes with the cortisol secretion parameters and the presence/absence of GC sensitizing GR polymorphisms and the degree of 11HSD2 activity, will be evaluated.
An algorithm for predicting the effect of the surgical or conservative approach on the primary outcomes in the individual AI patient with uncertain SH. The algorithm, based on the combination of the SH complications at baseline (hypertension, osteoporotic fractures, diabetes) with the presence/absence of GC sensitizing GR polymorphisms, degree of 11HSD2 activity and parameters of cortisol secretion, will be retrospectively tested on the study population, will be elaborated. This would consent to evaluate positive and negative predictive value of the algorithm for predicting the response to surgery in the individual patient with AI.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A, surgery | Experimental | Procedure: adrenalectomyadrenalectomy |
| B, observation | No intervention | –conservative follow up |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- unilateral adrenal incidentaloma larger than 1 cm
- cortisol after 1-mg overnight dexamethasone suppression test (1mgDST) between 1.8 and 5 mcg/dl
Key exclusion criteria (6 listed)
- hypogonadism, thyrotoxicosis, chronic renal failure and hepatic disease, alcoholism, eating, rheumatologic or hematological disorders;
- intake of drugs influencing cortisol and dexamethasone metabolism or cortisol secretion;
- signs of hypercortisolism (moon facies, striae rubrae, easy bruising);
- possible metastatic disease or radiologic features not consistent with adrenocortical adenoma at computed tomography (CT);
- pheochromocytoma and aldosteronoma;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| adrenalectomy | Procedure or surgery | A, surgery |
Primary outcome
variation of blood pressure
Time frame: 6 months
To assess the variation of blood pressure ambulatory systolic and diastolic blood pressure (BP, mmHg), and antihypertensive treatment at baseline and follow-up will be assessed; BP will be considered improved or worsened if the non-hypertensive patients passed from a pre-hypertension category to another or the hypertensive patients from a hypertension grade to another in accordance to giudelines, of if if antihypertensive treatment was reduced by 50%
variation of glucose levels
Time frame: 6 months
To assess the variation of glucose levels, fasting glucose levels and glucose levels after oral glucose tolerance test will be evaluated at baseline and follow-up. Glucose levels will be considered improved or worsened if fasting glucose levels pass from a category to another, following the Adult Treatment Panel III criteria or if antidiabetic treatment was reduced by 50%
variation of lipids
Time frame: 6 months
At baseline and follow up triglyceride levels; total cholesterol levels, HDL and LDL levels (mg/dl) will be evaluated. Dyslipidemia will be diagnosed in the presence of triglyceride levels >150 mg/dl or high-density lipoprotein (HDL) cholesterol levels <40 or 50 mg/dl in males and females. dyslipidemia will be defined improved or worsened if cholesterol levels pass from a category to another, following the Adult Treatment Panel III criteria
variation of body weight
Time frame: 6 months
At baseline and follow up body weight (kilograms) will be evaluated. the improvement/worsening during follow-up will be defined in the presence of a >5% BW decrease/increase
variation of bone mineral density (BMD)
Time frame: 24 months
To assess the variation of bone mineral density at baseline and follow-up a Dual-energy X-ray absorptiometry (DXA) scan will be performed
occurrence of vertebral fractures
Time frame: 24 months
A dorso-lumbar spine x-ray to evaluate the presence of morphometric fractures (presence/absence) will be performed
variation of intimal medial thickness
Time frame: 12 months
To assess the variation of vascular damage a supra-aortic trunk echo-Doppler to evaluate at baseline and follow-up variations of intimal medial thickness will be performed
variation of Relative wall thickness (RWT)
Time frame: 12 months
the variation of Relative wall thickness (RWT) will be evaluated by an echocardiography. It will be calculated from Left ventricular end diastolic dimension (LVEDD) (mm); Interventricular septal end diastole (IV Sd, mm) and Posterior wall thickness at end-diastole (PWd) parameters (mm)
variation of Sheehan Disability Scale
Time frame: 6 months
Sheehan Disability Scale will be evaluated to assess perceived stress (SDS-stress scale ranges 1-10, a higher score means higher levels of stress)
Cognitive evaluation by Brief Assessment Cognition in Schizophrenia (BACS) score
Time frame: 6 months
BACS evaluate verbal memory score (normal if >33); working memory (normal if >14.9); verbal fluency (normal if >31.6), symbol coding (normal if >40.5), tower of london (>12.4)
2 secondary outcomes
cortisol secretion and sensitivity
Time frame: 24 months
variation of Inflammation markers and bone metabolism markers
Time frame: 6 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Apr 2021.
- Background: PubMed 10732263Reincke M. Subclinical Cushing's syndrome. Endocrinol Metab Clin North Am. 2000 Mar;29(1):43-56. doi: 10.1016/s0889-8529(05)70115-8.
- Background: PubMed 15850851Terzolo M, Bovio S, Reimondo G, Pia A, Osella G, Borretta G, Angeli A. Subclinical Cushing's syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am. 2005 Jun;34(2):423-39, x. doi: 10.1016/j.ecl.2005.01.008.
- Background: PubMed 19549741Chiodini I, Morelli V, Masserini B, Salcuni AS, Eller-Vainicher C, Viti R, Coletti F, Guglielmi G, Battista C, Carnevale V, Iorio L, Beck-Peccoz P, Arosio M, Ambrosi B, Scillitani A. Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian multicenter study. J Clin Endocrinol Metab. 2009 Sep;94(9):3207-14. doi: 10.1210/jc.2009-0468. Epub 2009 Jun 23.
- Background: PubMed 24423350Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, Salcuni AS, Dolci A, Mendola M, Arosio M, Ambrosi B, Scillitani A, Ghigo E, Beck-Peccoz P, Terzolo M, Chiodini I. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab. 2014 Mar;99(3):827-34. doi: 10.1210/jc.2013-3527. Epub 2014 Jan 1.
- Background: PubMed 24795253Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E, Mosconi C, Golfieri R, Paccapelo A, Pagotto U, Pasquali R. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol. 2014 May;2(5):396-405. doi: 10.1016/S2213-8587(13)70211-0. Epub 2014 Jan 29.
- Background: PubMed 19906240Manenschijn L, van den Akker EL, Lamberts SW, van Rossum EF. Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Ann N Y Acad Sci. 2009 Oct;1179:179-98. doi: 10.1111/j.1749-6632.2009.05013.x.
- Background: PubMed 19207316Szappanos A, Patocs A, Toke J, Boyle B, Sereg M, Majnik J, Borgulya G, Varga I, Liko I, Racz K, Toth M. BclI polymorphism of the glucocorticoid receptor gene is associated with decreased bone mineral density in patients with endogenous hypercortisolism. Clin Endocrinol (Oxf). 2009 Nov;71(5):636-43. doi: 10.1111/j.1365-2265.2009.03528.x. Epub 2009 Jan 22.
- Background: PubMed 15466942Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004 Oct;25(5):831-66. doi: 10.1210/er.2003-0031.
- Background: PubMed 22549969Eller-Vainicher C, Morelli V, Ulivieri FM, Palmieri S, Zhukouskaya VV, Cairoli E, Pino R, Naccarato A, Scillitani A, Beck-Peccoz P, Chiodini I. Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism. J Bone Miner Res. 2012 Oct;27(10):2223-30. doi: 10.1002/jbmr.1648.
- Background: PubMed 18426820Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, Pivonello R, Stalla G, Lamberts SW, Glusman JE. Evaluation of health-related quality of life in patients with Cushing's syndrome with a new questionnaire. Eur J Endocrinol. 2008 May;158(5):623-30. doi: 10.1530/EJE-07-0762.
- Background: PubMed 12502614Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003 Jan;26 Suppl 1:S5-20. doi: 10.2337/diacare.26.2007.s5. No abstract available.
- Background: PubMed 11368702Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97. doi: 10.1001/jama.285.19.2486. No abstract available.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Iacopo Chiodini, Professor principal investigator
Istituto Auxologico Italiano
Questions about this trial
What is this clinical trial studying?
A study testing adrenalectomy in people with Adrenal Incidentaloma and Subclinical Hypercortisolism, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 26 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
variation of blood pressure (time frame: 6 months). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04860180, which also lists 18 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Apr 2021.