Adrenal IncidentalomaNCT03919734
Morbidity and Mortality in Autonomous Cortisol Secretion
An observational study of Adrenal Incidentaloma and Cortisol Overproduction, run by Region Skane at 1 site in Sweden.
Trial summary
Benign enlargements of the adrenal glands (adrenal adenomas) are frequent in adults. In the general population these adenomas are rare in subjects below 40 years of age but at the age of 60 and 80 years the prevalence is 6 and 8-10 % respectively. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adrenal Incidentaloma, Cortisol Overproduction
- How many people
- 4,596 participants
- Where
- 1 siteSweden
- Study dates
- 15 Sep 2015to 3 Jan 2020
- Phase
- Observational
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients examined at the Endocrine outpatient ambulatory first time for adrenal incidentalomas during the period from January 1, 2005 to September 15, 2015. A Group of Age and sex matched controls developed by SCB.
Who may be able to join
- Patients with adrenal incidentalomas examined at Skane University Hospital and Helsingborg Hospital during the period from January 1, 2005 to September 15, 2015.
Who cannot join
- Size of incidentaloma below 1 cm
- Malignant disease with metastases,
- Incidentaloma not an adenoma but for example malignancy, myelolipoma and bleedings
- Pheochromocytomas
- Primary aldosteronism
- Continuous treatment with systemic glucocorticoid under the last 3 months.
Show all 9Show fewer
- Cushing Syndrome
- Medication affecting dexamethasone metabolism.
- Treatment with systemic estrogen
Trial locations and contacts
1 site in 1 country.
Sweden1 site
Dept. of Endocrinology, Skåne University Hospital
Lund, Skåne County, 25656
About this study
Official title: Morbidity and Mortality in Patients With Adrenal Incidentalomas With and Without Autonomous Cortisol Secretion
Benign enlargements of the adrenal glands (adrenal adenomas) are frequent in adults. In the general population these adenomas are rare in subjects below 40 years of age but at the age of 60 and 80 years the prevalence is 6 and 8-10 % respectively. Since these adenomas do not causes obvious symptoms they are almost exclusively found incidentally in patients examined radiologically for other reasons than suspected adrenal disease. These enlargements are thus termed adrenal incidentalomas (AI). AI may secrete cortisol and more than 25 percent of patients with an AI have increased cortisol levels called autonomous cortisol secretion (ACS). Such increased secretion of cortisol may cause metabolic complications such as hypertension, high cholesterol, diabetes and cardiovascular disease. Studies have shown that ACS may cause increased mortality. These studies are however small and have not adequately taking other conditions into account which most likely influences the result.
The investigators hypothesis is that ACS is linked to increased mortality as the previous studies have shown. The aim is to perform a larger study on patients with adrenal incidentalomas, both with and without ACS, and compare the mortality rates with a control group matched for age and sex. This study may more precisely describe the cardiovascular risk for ACS and define the risk at different levels of ACS.
Read the detailed description
Patients with adrenal adenomas may have autonomous cortisol secretion (ACS) that has been linked to hypertension, diabetes, dyslipidemia and cardiovascular disease. Patients with ACS also have been found to have increased mortality. In two studies the excess mortality was caused by cardiovascular disease and in one study by cancer.
ACS is diagnosed by increased cortisol (≥50 nmol/l) following 1-mg dexamethasone suppression (DST) often in combination with another confirmatory test such as low ACTH, increased urinary cortisol, increased midnight salivary cortisol or a dexamethasone suppression test with a higher dexamethasone dose. Cortisol secretion from an AI has been considered exclusively autonomous but the investigators have recently shown that a large group of patients with normal results on DST have low ACTH indicating that another factor than ACS may suppress the HPA-axis. The hypothesis is that these patients have an increased sensitivity to ACTH, which results in lower ACTH levels. It has however not been studied whether the increased sensitivity to ACTH is linked to increased cardiovascular morbidity and mortality.
Patient data is collected from the patient cards and radiology images. Patients are included according to the eligibility criteria. The patients will be separated in the following groups:
- No ACS, inhalation steroids or adrenalectomy.
- ACS/possible-ACS but not treatment with inhalation steroids or adrenalectomy
- Treatment inhalation steroids but not operated.
- Unilateral AI and treated with adrenalectomy but no inhalation steroids. The group is separated in patients without ACS and patients with possible ACS/ACS.
Three age and gender matched subjects from the general population for every patient will serve as a controls.
Outcome data on patients and controls is received from The National Board of Health and Welfare. The control group is achieved from SCB, Sweden (Statistics Sweden). The following outcome data will be collected: Data on mortality, cause of mortality and inpatient and outpatient cardiovascular diagnoses. The study design reduces the risk for bias between the clinical endpoints and the patient's cortisol and ACTH levels. The patient cohorts will be finally defined before the investigators receive the clinical endpoints from The National Board of Health and Welfare.
Statistical analysis: The prevalence of the outcome data in the groups of patients will be compared. The investigators will adjusted for differences between the groups in sex, age, smoking, impaired renal function, and existing cardiovascular disease.
The following variables will be examined in relation to the outcome data: Cortisol following dexamethasone (≥50 nmol/l, ≥83 nmol/l and ≥138 nmol/l), low basal ACTH (<2.0 pmol/l), DHEAS, the size of the AI and bilateral versus unilateral AI.
Study Status: We anticipate to receive the outcome data from The National Board of Health and Welfare in October 2019. The study has thus been slightly delayed. Data on morbidity will only be available until December 31, 2017 due to a delay in reporting to The National Board of Health and Welfare. The secondary outcome measure has been changed to a composite of cardiovascular endpoints.
- Conditions
- Adrenal Incidentaloma, Cortisol Overproduction
- Medical subject headings
- Adrenal incidentaloma, ACTH Syndrome, Ectopic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| AI ACS/possible ACS | Patients with adrenal incidentalomas and cortisol following overnight 1-mg dexamethasone suppression equal to or above 50 nmol/l. The patients should not have clinical signs of Cushing Syndrome, such as catabolic skin and muscle changes. | |
| AI non-ACS | Patients with adrenal incidentalomas and cortisol following overnight 1-mg dexamethasone suppression below 50 nmol/l. | |
| Treatment with Inhalation Steroids | Patients treated with inhalation steroids with and without ACS/possible ACS but not operated with adrenalectomy. | |
| Adrenalectomy | Patients with unilateral AI operated with adrenalectomy | |
| Controls | A Group of Controls matched for sex and age, achieved by the government agency "Statistics Sweden" (SCB). |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients deceased, both totally and divided into three specified diagnose groups (cardiovascular disease, infections and cancer).
The cause of death is defined by the ICD-10 code reported by The National Board of Health and Welfare.
Measured: From date of enrollment until December 31, 2018.
Secondary outcomes (1)
A composite of cardiovascular death, nonfatal myocardial infarction (excluding silent myocardial infarction), nonfatal stroke, hospitalization for heart failure and revascularization (CABG and PCI). The endpoints will also be calculated separately.
The diagnoses is defined by the ICD-10 code and Swedish classification of healthcare interventions (KVÅ-codes FNA-FNG) both reported by The National Board of Health and Welfare
Measured: From date of enrollment until December 31, 2017.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2019
- Study start15 Sep 2015
- Primary completion3 Jan 2020
- Study completion3 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Adrenal IncidentalomaStudies of the same condition, open and under way.
- 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
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 4,596 participants (actual)
Sponsor and investigators
- Lead sponsor
- Region Skane
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Henrik Olsen, Region Skane
- Investigators
- Henrik Olsen, MD, PhD, Principal investigator, Medical Faculty, University of Lund
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03919734
- Sponsor's protocol ID
- 1
- Status last verified
- Mar 2021
- First submitted
- 7 Apr 2019
- Last updated
- 26 Mar 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug;175(2):G1-G34. doi: 10.1530/EJE-16-0467.
PubMed 27390021Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J. Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J Clin Endocrinol Metab. 2014 Dec;99(12):4462-70. doi: 10.1210/jc.2014-3007.
PubMed 25238207Di 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 24795253Patrova J, Kjellman M, Wahrenberg H, Falhammar H. Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. Endocrine. 2017 Nov;58(2):267-275. doi: 10.1007/s12020-017-1400-8. Epub 2017 Sep 8.
PubMed 28887710Olsen H, Kjellbom A, Londahl M, Lindgren O. Suppressed ACTH Is Frequently Unrelated to Autonomous Cortisol Secretion in Patients With Adrenal Incidentalomas. J Clin Endocrinol Metab. 2019 Feb 1;104(2):506-512. doi: 10.1210/jc.2018-01029.
PubMed 30265354Kjellbom A, Lindgren O, Danielsson M, Olsen H, Londahl M. Mortality Not Increased in Patients With Nonfunctional Adrenal Adenomas: A Matched Cohort Study. J Clin Endocrinol Metab. 2023 Jul 14;108(8):e536-e541. doi: 10.1210/clinem/dgad074.
PubMed 36800277Kjellbom A, Lindgren O, Puvaneswaralingam S, Londahl M, Olsen H. Association Between Mortality and Levels of Autonomous Cortisol Secretion by Adrenal Incidentalomas : A Cohort Study. Ann Intern Med. 2021 Aug;174(8):1041-1049. doi: 10.7326/M20-7946. Epub 2021 May 25.
PubMed 34029490
Study at a glance
From the registry record, last updated by the sponsor on 26 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Morbidity and Mortality in Patients With Adrenal Incidentalomas With and Without Autonomous Cortisol Secretion
- ClinicalTrials.gov ID
- NCT03919734
- Acronym / sponsor ID
- 1
- Conditions
- Adrenal Incidentaloma, Cortisol Overproduction
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 4,596 participants (actual)
- Lead sponsor
- Region SkaneUniversity, hospital or other
- Study start
- 15 Sep 2015 (actual)
- Primary completion
- 3 Jan 2020 (actual)
- Study completion
- 3 Jan 2020 (actual)
- First posted
- 18 Apr 2019 (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.
Benign enlargements of the adrenal glands (adrenal adenomas) are frequent in adults. In the general population these adenomas are rare in subjects below 40 years of age but at the age of 60 and 80 years the prevalence is 6 and 8-10 % respectively. Since these adenomas do not causes obvious symptoms they are almost exclusively found incidentally in patients examined radiologically for other reasons than suspected adrenal disease. These enlargements are thus termed adrenal incidentalomas (AI). AI may secrete cortisol and more than 25 percent of patients with an AI have increased cortisol levels called autonomous cortisol secretion (ACS). Such increased secretion of cortisol may cause metabolic complications such as hypertension, high cholesterol, diabetes and cardiovascular disease. Studies have shown that ACS may cause increased mortality. These studies are however small and have not adequately taking other conditions into account which most likely influences the result.
The investigators hypothesis is that ACS is linked to increased mortality as the previous studies have shown. The aim is to perform a larger study on patients with adrenal incidentalomas, both with and without ACS, and compare the mortality rates with a control group matched for age and sex. This study may more precisely describe the cardiovascular risk for ACS and define the risk at different levels of ACS.
Detailed description
Patients with adrenal adenomas may have autonomous cortisol secretion (ACS) that has been linked to hypertension, diabetes, dyslipidemia and cardiovascular disease. Patients with ACS also have been found to have increased mortality. In two studies the excess mortality was caused by cardiovascular disease and in one study by cancer.
ACS is diagnosed by increased cortisol (≥50 nmol/l) following 1-mg dexamethasone suppression (DST) often in combination with another confirmatory test such as low ACTH, increased urinary cortisol, increased midnight salivary cortisol or a dexamethasone suppression test with a higher dexamethasone dose. Cortisol secretion from an AI has been considered exclusively autonomous but the investigators have recently shown that a large group of patients with normal results on DST have low ACTH indicating that another factor than ACS may suppress the HPA-axis. The hypothesis is that these patients have an increased sensitivity to ACTH, which results in lower ACTH levels. It has however not been studied whether the increased sensitivity to ACTH is linked to increased cardiovascular morbidity and mortality.
Patient data is collected from the patient cards and radiology images. Patients are included according to the eligibility criteria. The patients will be separated in the following groups:
- No ACS, inhalation steroids or adrenalectomy.
- ACS/possible-ACS but not treatment with inhalation steroids or adrenalectomy
- Treatment inhalation steroids but not operated.
- Unilateral AI and treated with adrenalectomy but no inhalation steroids. The group is separated in patients without ACS and patients with possible ACS/ACS.
Three age and gender matched subjects from the general population for every patient will serve as a controls.
Outcome data on patients and controls is received from The National Board of Health and Welfare. The control group is achieved from SCB, Sweden (Statistics Sweden). The following outcome data will be collected: Data on mortality, cause of mortality and inpatient and outpatient cardiovascular diagnoses. The study design reduces the risk for bias between the clinical endpoints and the patient's cortisol and ACTH levels. The patient cohorts will be finally defined before the investigators receive the clinical endpoints from The National Board of Health and Welfare.
Statistical analysis: The prevalence of the outcome data in the groups of patients will be compared. The investigators will adjusted for differences between the groups in sex, age, smoking, impaired renal function, and existing cardiovascular disease.
The following variables will be examined in relation to the outcome data: Cortisol following dexamethasone (≥50 nmol/l, ≥83 nmol/l and ≥138 nmol/l), low basal ACTH (<2.0 pmol/l), DHEAS, the size of the AI and bilateral versus unilateral AI.
Study Status: We anticipate to receive the outcome data from The National Board of Health and Welfare in October 2019. The study has thus been slightly delayed. Data on morbidity will only be available until December 31, 2017 due to a delay in reporting to The National Board of Health and Welfare. The secondary outcome measure has been changed to a composite of cardiovascular endpoints.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| AI ACS/possible ACS | – | –Patients with adrenal incidentalomas and cortisol following overnight 1-mg dexamethasone suppression equal to or above 50 nmol/l. The patients should not have clinical signs of Cushing Syndrome, such as catabolic skin and muscle changes. |
| AI non-ACS | – | –Patients with adrenal incidentalomas and cortisol following overnight 1-mg dexamethasone suppression below 50 nmol/l. |
| Treatment with Inhalation Steroids | – | –Patients treated with inhalation steroids with and without ACS/possible ACS but not operated with adrenalectomy. |
| Adrenalectomy | – | –Patients with unilateral AI operated with adrenalectomy |
| Controls | – | –A Group of Controls matched for sex and age, achieved by the government agency "Statistics Sweden" (SCB). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients examined at the Endocrine outpatient ambulatory first time for adrenal incidentalomas during the period from January 1, 2005 to September 15, 2015. A Group of Age and sex matched controls developed by SCB.
Key inclusion criteria (1 listed)
- Patients with adrenal incidentalomas examined at Skane University Hospital and Helsingborg Hospital during the period from January 1, 2005 to September 15, 2015.
Key exclusion criteria (9 listed)
- Size of incidentaloma below 1 cm
- Malignant disease with metastases,
- Incidentaloma not an adenoma but for example malignancy, myelolipoma and bleedings
- Pheochromocytomas
- Primary aldosteronism
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Number of patients deceased, both totally and divided into three specified diagnose groups (cardiovascular disease, infections and cancer).
Time frame: From date of enrollment until December 31, 2018.
The cause of death is defined by the ICD-10 code reported by The National Board of Health and Welfare.
1 secondary outcome
A composite of cardiovascular death, nonfatal myocardial infarction (excluding silent myocardial infarction), nonfatal stroke, hospitalization for heart failure and revascularization (CABG and PCI). The endpoints will also be calculated separately.
Time frame: From date of enrollment until December 31, 2017.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Mar 2021.
- Background: PubMed 27390021Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug;175(2):G1-G34. doi: 10.1530/EJE-16-0467.
- Background: PubMed 25238207Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J. Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J Clin Endocrinol Metab. 2014 Dec;99(12):4462-70. doi: 10.1210/jc.2014-3007.
- 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 28887710Patrova J, Kjellman M, Wahrenberg H, Falhammar H. Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. Endocrine. 2017 Nov;58(2):267-275. doi: 10.1007/s12020-017-1400-8. Epub 2017 Sep 8.
- Background: PubMed 30265354Olsen H, Kjellbom A, Londahl M, Lindgren O. Suppressed ACTH Is Frequently Unrelated to Autonomous Cortisol Secretion in Patients With Adrenal Incidentalomas. J Clin Endocrinol Metab. 2019 Feb 1;104(2):506-512. doi: 10.1210/jc.2018-01029.
- Derived from this study: PubMed 36800277Kjellbom A, Lindgren O, Danielsson M, Olsen H, Londahl M. Mortality Not Increased in Patients With Nonfunctional Adrenal Adenomas: A Matched Cohort Study. J Clin Endocrinol Metab. 2023 Jul 14;108(8):e536-e541. doi: 10.1210/clinem/dgad074.
- Derived from this study: PubMed 34029490Kjellbom A, Lindgren O, Puvaneswaralingam S, Londahl M, Olsen H. Association Between Mortality and Levels of Autonomous Cortisol Secretion by Adrenal Incidentalomas : A Cohort Study. Ann Intern Med. 2021 Aug;174(8):1041-1049. doi: 10.7326/M20-7946. Epub 2021 May 25.
- Individual participant dataSharing planned: No
Related trials for Adrenal Incidentaloma
RecruitingObservational study
Clinical and Molecular Characteristics of Primary Aldosteronism in Blacks
Adrenal Gland Neoplasm, Hypertension
RecruitingPhase 4
Isturisa Treatment in Mild Autonomous Cortisol Secretion( MACS)
Mild Autonomous Cortisol Secretion (MACS)
RecruitingObservational study
Cardiovascular Complications After Adrenalectomy for Pheochromocytoma and Non-secreting Tumors
Pheochromocytoma, Cardiovascular Complication
Active, not recruitingPhase 2
Extension Study to Evaluate the Safety of Long-Term Use of Relacorilant in Patients With Cushing Syndrome
Cushing Syndrome
Active, not recruitingPhase 2
Metyrapone for Mild Autonomous Cortisol Secretion (MACS)
Autonomous Cortisol Secretion, Mild Autonomous Cortisol Secretion (MACS)
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.
Henrik Olsen, MD, PhD principal investigator
Medical Faculty, University of Lund
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Adrenal Incidentaloma and Cortisol Overproduction, run by Region Skane at 1 site in Sweden.
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 1 inclusion and 9 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: finished, as of the sponsor's last update on 26 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Number of patients deceased, both totally and divided into three specified diagnose groups (cardiovascular disease, infections and cancer). (time frame: From date of enrollment until December 31, 2018.). 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 NCT03919734, which also lists 7 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 Mar 2021.