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Trial registered on ANZCTR


Registration number
ACTRN12620000654954
Ethics application status
Approved
Date submitted
14/05/2020
Date registered
5/06/2020
Date last updated
5/06/2020
Date data sharing statement initially provided
5/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Cardio-metabolic consequences of mild adrenal glucocorticoid excess
Scientific title
Cardio-metabolic consequences of mild adrenal glucocorticoid excess
Secondary ID [1] 299982 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
adrenal adenoma 315449 0
cardio-metabolic disease 315450 0
Condition category
Condition code
Metabolic and Endocrine 313751 313751 0 0
Other endocrine disorders
Metabolic and Endocrine 313752 313752 0 0
Metabolic disorders
Cardiovascular 315685 315685 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients with incidentally identified adrenal adenoma (adrenal incidentaloma), and low excess cortisol secretion, defined as morning cortisol concentration 50 - 140 nmol/L after 1 mg dexamethasone will identified. Dexamethasone is administered via oral capsule as part of routine clinical care to evaluate for autonomous cortisol secretion in all patients with adrenal incidentaloma. As such, prior to study enrolment, patients will have had this test performed by their usual endocrinologist or treating physician.

Study investigators will review incoming referrals to the Endocrine Department at Flinders Medical Centre and the Lyell McEwin Hospital to identify potential participants who have adrenal incidentaloma and have already had a 1mg dexamethasone test performed to identify patients with adrenal incidentaloma and mild autonomous cortisol secretion and a control group of patients with non-functioning adrenal incidentaloma.

Participant commitment will consist of one study visit to the Endocrine Research Unit lasting 5-6 hours and 24 hour blood pressure monitoring on one occasion only. Following a 10 hour overnight fast, participants will attend the Endocrine Research Unit at Southern Adelaide Diabetes and Endocrine Services at 0800 on the study day. Baseline anthropometric measures including height, weight and waist circumference will be collected. An intravenous cannula will be inserted into the antecubital fossa and baseline blood samples for glycated haemoglobin (HbA1c), insulin and glucose will be collected.

The following investigative procedures will be performed:
1. Endothelial function, will be evaluated via peripheral arterial tonometry. This will be performed using an Endo-Pat 2000 device (Itamar Medical). A finger plethysmograph will be placed on each hand. This will record finger arterial pulsatile volume changes. Baseline readings will be performed, after which local ischaemia is induced in one arm by inflating a blood pressure cuff to suprasystolic pressures for 5 mins. The blood pressure cuff will then be deflated, and the change in pulse amplitude will be used to estimate endothelial function.

2. Insulin sensitivity, will be estimated from measurements of glucose and insulin before and every 30 minutes for 2 hours after a mixed meal (10kcal/kg, 45% carbohydrate, 15% protein, 40% fat) using the Matsuda index.

3. Fat oxidation, will be evaluated using indirect calorimetry which will be performed using a ventilated hood technique (Parvo Medics True One 2400 Metabolic Measurement System, Parvo Medics, Sandy, UT). This will be performed fasting and 120 mins following the meal. Indirect calorimetry is the method by which type and rate of substrate utilisation and energy metabolism is estimated from gas exchange measurements. Substrate oxidation and resting energy expenditure will be calculated using equations of Ferrannini. Diet-induced thermogenesis will be calculated as the percentage increase in energy expenditure after the mixed-meal.

4. Body composition and bone mineral density at the hip and spine, will be quantified by dual energy X-ray (DEXA), which will quantify lean body mass, total fat mass and central abdominal fat and bone mineral density.

5. 24 hour ambulatory blood pressure, will be evaluated using oscillometric methods using the Mobil-O-Graph PWA (I.E.M. GmbH, Germany). Blood pressure cuff will be worn for 24 hours on the upper arm and blood pressure measurements will be taken every hour. Participants will commence 24 hour ambulatory blood pressure monitoring at the completion of the study day outlined above and will return it to SADES the following day.
Intervention code [1] 316251 0
Diagnosis / Prognosis
Comparator / control treatment
Patients with incidentally identified adrenal adenoma, who do not have excess cortisol secretion, defined as morning cortisol concentration < 50 nmol/L after 1 mg dexamethasone.

As with patients allocated as the "cases" group, 1mg dexamethasone suppression test will also have been performed prior to study enrollment for the "controls" group as the 1mg dexamethasone suppression test is performed as part of routine clinical case to evaluate for autonomous cortisol secretion in patients with adrenal adenoma.

Patients allocated to the "controls" group will undergo the exact same study day procedures as outlined

Control patients will participate in a study to investigate their cardio-metabolic function, that consists of exactly the same study day procedures as described for the cases,
Control group
Active

Outcomes
Primary outcome [1] 322163 0
The primary end point is the difference in reactive hyperaemia index between controls with cortisol concentration < 50 nmol/L and cases with cortisol concentration between 50-140 nmol/L.. Reactive hyperaemia is surrogate marker for endothelial function, which will be evaluated via peripheral arterial tonometry. This will be performed using an Endo-Pat 2000 device (Itamar Medical). A finger plethysmograph will be placed on each hand. This will record finger arterial pulsatile volume changes. Baseline readings will be performed, after which local ischaemia is induced in one arm by inflating a blood pressure cuff to suprasystolic pressures for 5 mins. The blood pressure cuff will then be deflated, and the change in pulse amplitude will be used to estimate endothelial function. This will be performed 60 minutes before and 60 minutes after the meal.
Timepoint [1] 322163 0
The primary time end-point is a comparator between baseline measurements and repeat measurements of the various indices after a meal. This will finish at the end of the study day. As dexamethasone suppression test is performed independently of the study day, primary timepoint is not related to dexamethasone administration.
Secondary outcome [1] 377548 0
A secondary end-point is the simple linear relationship between reactive hyperaemia index and cortisol after dexamethasone. As with the primary endpoint, reactive hyperaemia will assessed with EndoPat techniques as described in the primary outcome.
Timepoint [1] 377548 0
The secondary time end-point is a comparator between baseline measurements and repeat measurements of the various indices after a meal. This will finish at the end of the study day. As dexamethasone suppression test is performed independently of the study day, primary timepoint is not related to dexamethasone administration.
Secondary outcome [2] 383331 0
Difference in insulin sensitivity at baseline and after a meal between cases and controls, as estimated via Matsuda index, Insulin sensitivity will be estimated from measurements of glucose and insulin before a mixed meal and every 30 minutes for 2 hours after a mixed meal (10kcal/kg, 45% carbohydrate, 15% protein, 40% fat) using the Matsuda index.
Timepoint [2] 383331 0
Comparisons will be made between insulin sensitivity at baseline and 2 hours after the mixed-meal.
Secondary outcome [3] 383332 0
Difference in fat oxidation at baseline and 2 hours after a meal between cases and controls. Fat oxidation will be evaluated using indirect calorimetry which will be performed using a ventilated hood technique (Parvo Medics True One 2400 Metabolic Measurement System, Parvo Medics, Sandy, UT). This will be performed fasting and 2 hours following the meal.
Timepoint [3] 383332 0
Comparisons will be made between insulin sensitivity at baseline and 2 hours after the mixed-meal.
Secondary outcome [4] 383333 0
Difference in body composition and bone mineral density at the hip and spine between cases and controls. This will be quantified by dual energy X-ray (DEXA), which will quantify lean body mass, total fat mass and central abdominal fat and bone mineral density.
Timepoint [4] 383333 0
This will be a baseline measurement that is taken at the end of the study day.
Secondary outcome [5] 383334 0
Difference in baseline markers of cardio-metabolic function including HbA1c, insulin, glucose, DHEA between cases and controls.
Timepoint [5] 383334 0
These will be baseline blood investigations that are performed at the start of the study day.

Eligibility
Key inclusion criteria
- Adrenal adenoma incidentally identified on computer tomography scan of the abdomen to investigate some other unrelated complaint
- Morning cortisol between 50 - 140 nmol/L after 1mg dexamthasone suppression test (Group 1)
- Morning cortisol < 50 nmol/L after 1mg dexamethasone suppression test (Group 2)
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prescribed oral prednisolone, hydrocortisone or dexamethasone in the last 6 months
2. Regular inhaled glucocorticoid therapy
3. Regular oral oestrogen, phenytoin or carbamazepine therapy
4. Pregnancy
5. Uncontrolled depression or depressive illness

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis
For comparison of insulin sensitivity, substrate oxidation, endothelial function and 24-hour blood pressure monitoring between participant groups simple linear regression analyses of the relationship between cortisol after dexamethasone and cardio-metabolic endpoints will be performed. A sample size of 40 participants has 80% power to detect a difference in reactive hyperaemia index (RHI) of 0.45 between the two groups at the 0.05 significance level. This calculation assumes a standard deviation for (RHI) of 0.5, derived from a previous study. Moreover, a sample size of 40 participants gives 80% power to detect an effect of association with r-value 0.45 between cortisol after dexamethasone and reactive hyperaemia index, at the two-tailed 0.05 significance level.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 15382 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 15383 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment postcode(s) [1] 28699 0
5042 - Bedford Park
Recruitment postcode(s) [2] 28700 0
5112 - Elizabeth Vale

Funding & Sponsors
Funding source category [1] 304440 0
Charities/Societies/Foundations
Name [1] 304440 0
Endocrine Society of Australia
Address [1] 304440 0
145 Macquarie Street
Sydney. NSW. 2000.
Country [1] 304440 0
Australia
Funding source category [2] 304442 0
Charities/Societies/Foundations
Name [2] 304442 0
Flinders Foundation
Address [2] 304442 0
Flinders Drive
Bedford Park, SA, 5042
Country [2] 304442 0
Australia
Primary sponsor type
Individual
Name
Morton Burt
Address
SA Diabetes and Endocrinology Services,
10 Milham Street
Oaklands Park, SA, 5046
Country
Australia
Secondary sponsor category [1] 306151 0
None
Name [1] 306151 0
Address [1] 306151 0
Country [1] 306151 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304875 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 304875 0
Flinders Medical Centre, Ward 6C, Room 6A219
Flinders Drive
Bedford Park, SA 5042
Ethics committee country [1] 304875 0
Australia
Date submitted for ethics approval [1] 304875 0
08/10/2019
Approval date [1] 304875 0
02/12/2019
Ethics approval number [1] 304875 0
212.19

Summary
Brief summary
In up to 5% of the population, a benign adrenal adenoma is identified when abdominal computer tomography (CT) scans are performed for an unrelated complaint. Many of these adenomas secrete low levels of excess cortisol (a steroid hormone). Although mild excess cortisol secretion has been linked to adverse cardio-metabolic effects and death, the mechanisms underlying this association have not been fully evaluated. This study aims to investigate and determine the mechanisms that underlie the association between low level cortisol excess and increased cardio-metabolic risk.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes
N/A

Contacts
Principal investigator
Name 98494 0
A/Prof Morton Burt
Address 98494 0
SA Diabetes and Endocrinology Services,
Marion GP Plus
10 Milham Street
Oaklands Park, SA, 5046
Country 98494 0
Australia
Phone 98494 0
+61416125288
Fax 98494 0
Email 98494 0
morton.burt@sa.gov.au
Contact person for public queries
Name 98495 0
Dr Angela Xun-Nan Chen
Address 98495 0
SA Diabetes and Endocrinology Services,
Marion GP Plus
10 Milham Street
Oaklands Park, SA, 5046
Country 98495 0
Australia
Phone 98495 0
+61416125288
Fax 98495 0
Email 98495 0
angelaxun-nan.chen@sa.gov.au
Contact person for scientific queries
Name 98496 0
Dr Angela Xun-Nan Chen
Address 98496 0
SA Diabetes and Endocrinology Services,
10 Milham Street
Oaklands Park, SA, 5046
Country 98496 0
Australia
Phone 98496 0
+61416125288
Fax 98496 0
Email 98496 0
angelaxun-nan.chen@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As some individual participant data may make participants identifiable, these will not be made publicly available. However, interested parties can contact the PI to access data as needed.
What supporting documents are/will be available?
No other documents available
Summary results
No Results