Screening and Stimulation Testing for Residual Secretion of Adrenal Steroid Hormones in Autoimmune Addison's Disease

NCT ID: NCT03793114

Last Updated: 2023-11-29

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-26
• Study Completion Date: 2025-12-31

Brief Summary

In autoimmune adrenal insufficiency, or Addison's disease (AD), the immune system attacks the adrenal cortex. As a result, the adrenal cells producing hormones such as cortisol and aldosterone are destroyed, leaving the body with insufficient levels to meet its needs. The common perception is that upon diagnosis of Addison's disease, basically all adrenal hormone production has ceased.

There have, however, been found a few individuals who preserve some residual secretion of cortisol even years after diagnosis. The objectives of this study is to find out how common it is, and to explore if residual function have impact on patient outcome. That is, do patients with and without residual function differ when it comes to quality of life, working ability, medication dosages, and risk of adrenal crisis?

Detailed Description

Autoimmune destruction of the adrenal cortex is the main cause of primary adrenal insufficiency (Addison's disease, AD). Autoimmune AD (AAD) becomes clinically manifest when 90 % of cortex of adrenal gland is destroyed. Current dogma says that adrenal insufficiency ultimately is complete, that is the adrenal cortex stops producing steroids altogether. However, several case reports indicate that there might be a subgroup of patients that retain some steroid production, even years after the diagnosis. This ability could be beneficial as it could protect against adrenal crises, ease medication, and leave the patient with better quality of life.

The objective of the study is to systematically assess to what extent patients with AAD have residual adrenocortical function, and to characterize this subgroup.

The study will be an open non-randomized three-stage multicenter clinical trial comprising patients from the Norwegian Registry for organ-specific autoimmune disease (ROAS), the Swedish Addison registry, and Germany. In stage 1, patients will be asked to fill out questionnaires and deliver medication-fasting samples for analyses of adrenal steroids. In addition, patients with congenital adrenal hyperplasia (CAH) and bilaterally adrenalectomized will serve as negative controls for adrenal steroids. In stage 2, AAD patients with residual steroid production will be invited to a cosyntropin stimulation test to estimate the maximum steroid output from the adrenal glands. Twenty patients with no sign of residual function will also be tested as a control group. In stage 3, AAD patients with confirmed residual function will be invited to go through a 30-hour ambulatory sampling of interstitial fluid for investigation of diurnal variation in adrenocortical hormone levels. Also, newly diagnosed AAD patients will be invited to repeated cosyntropin testing as a means of delineating the natural progression of adrenocortical failure.

Conditions

Primary Adrenal Insufficiency

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SCREENING
• Blinding Strategy: NONE

Study Groups

Detectable levels of adrenal hormones

Patients with detectable serum levels of adrenal hormones will go through cosyntropin stimulation testing.

Group Type: EXPERIMENTAL

Cosyntropin stimulation test

Intervention Type: DIAGNOSTIC_TEST

Blood samples are taken before (0 min), and 30 and 60 min after intravenously administration of 250 µg cosyntropin (tetracosactide acetate) with the patient placed in the recumbent position. The test will be performed non-fasting (but medication-fasting) between 08:00 and 10:00 a.m.

Controls with undetectable hormone levels

Twenty patients without detectable serum levels of adrenal hormones will serve as controls in cosyntropin stimulation testing.

Group Type: ACTIVE_COMPARATOR

Cosyntropin stimulation test

Intervention Type: DIAGNOSTIC_TEST

Blood samples are taken before (0 min), and 30 and 60 min after intravenously administration of 250 µg cosyntropin (tetracosactide acetate) with the patient placed in the recumbent position. The test will be performed non-fasting (but medication-fasting) between 08:00 and 10:00 a.m.

Undetectable levels of adrenal hormones

Patients without detectable serum levels of adrenal hormones. Cosyntropin stimulation testing will not be performed.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Congenital adrenal hyperplasia (CAH) control group

Mapping adrenal steroid profile in patients with congenital adrenal hyperplasia (CAH) with confirmed total deficiency of 21-hydroxylase.

Group Type: OTHER

Baseline blood tests

Intervention Type: DIAGNOSTIC_TEST

Medication-fasting morning levels of adrenocortical hormones.

Bilaterally adrenalectomized control group

Mapping adrenal steroid profile in patients who are bilaterally adrenalectomized.

Group Type: OTHER

Baseline blood tests

Intervention Type: DIAGNOSTIC_TEST

Medication-fasting morning levels of adrenocortical hormones.

Diurnal variation in residual adrenocortical hormone levels

Patients with detectable serum levels of adrenal hormones will go through a 30-hour ambulatory sampling of interstitial fluid for mapping of any diurnal variation in endogenous adrenocortical secretion.

Group Type: EXPERIMENTAL

30-hour ambulatory sampling of intestinal fluid

Intervention Type: DEVICE

30-hour ambulatory sampling of intestinal fluid for analysis of adrenocortical hormones.

Repeated cosyntropin testing in newly diagnosed patients

Newly diagnosed patients will be invited to go through repeated cosyntropin testing to delineate the natural progression of adrenocortical failure.

Group Type: EXPERIMENTAL

Cosyntropin stimulation test

Intervention Type: DIAGNOSTIC_TEST

Blood samples are taken before (0 min), and 30 and 60 min after intravenously administration of 250 µg cosyntropin (tetracosactide acetate) with the patient placed in the recumbent position. The test will be performed non-fasting (but medication-fasting) between 08:00 and 10:00 a.m.

Cardiovascular and inflammatory biomarkers

Compare cardiovascular and inflammatory biomarker profiles in patients with and without residual production of adrenocortical steroids

Group Type: ACTIVE_COMPARATOR

Blood test

Intervention Type: OTHER

Cardiovascular and inflammatory biomarker profiles

Interventions

Cosyntropin stimulation test

Blood samples are taken before (0 min), and 30 and 60 min after intravenously administration of 250 µg cosyntropin (tetracosactide acetate) with the patient placed in the recumbent position. The test will be performed non-fasting (but medication-fasting) between 08:00 and 10:00 a.m.

Intervention Type: DIAGNOSTIC_TEST

Baseline blood tests

Medication-fasting morning levels of adrenocortical hormones.

Intervention Type: DIAGNOSTIC_TEST

30-hour ambulatory sampling of intestinal fluid

30-hour ambulatory sampling of intestinal fluid for analysis of adrenocortical hormones.

Intervention Type: DEVICE

Blood test

Cardiovascular and inflammatory biomarker profiles

Intervention Type: OTHER

Other Intervention Names

Synacthen stimulation test

Eligibility Criteria

Inclusion Criteria

• Men and women with AAD, age 18-70 years old. This requires documented adrenal insufficiency and a positive test for 21-hydroxylase autoantibodies (biomarker for autoimmune cause) on at least one occasion.
• Provided written informed consent
• In case of concomitant endocrine/autoimmune diseases, the patients should be on stable adequate treatment at least the last 3 months prior to the study period.
• For Norwegian AD patients: enrolled in ROAS
• For Swedish AD patients: enrolled in the Swedish Addison registry

Exclusion Criteria

• Antihypertensive treatment, with the exception of doxazosin, verapamil, and moxonidine.
• Active malignant disease, severe heart, kidney or liver failure.
• Diabetes mellitus type 1.
• Pregnancy or breast feeding.
• Pharmacological treatment with glucocorticoids (except their usual cortisone or hydrocortisone replacement therapy) or drugs that interfere with cortisol and catecholamine metabolism (antiepileptics, rifampicin, St. Johns wart).
• Use of other glucocorticoid replacement medication than cortisone acetate or hydrocortisone.
• Intake of grapefruit, grapefruit juice, or and liquorice juice the last week before or during the study period.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Karolinska Institutet

OTHER

Sponsor Role: collaborator

Charite University, Berlin, Germany

OTHER

Sponsor Role: collaborator

University of Bergen

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eystein S Husebye, M.D, Prof

Role: PRINCIPAL_INVESTIGATOR

University of Bergen

Locations

Endokrinologie in Charlottenburg

Berlin, , Germany

Haukeland University Hospital

Bergen, , Norway

Karolinska Institutet

Stockholm, , Sweden

Countries

Germany; Norway; Sweden

References

Saevik AB, Akerman AK, Methlie P, Quinkler M, Jorgensen AP, Hoybye C, Debowska AJ, Nedrebo BG, Dahle AL, Carlsen S, Tomkowicz A, Sollid ST, Nermoen I, Gronning K, Dahlqvist P, Grimnes G, Skov J, Finnes T, Valland SF, Wahlberg J, Holte SE, Simunkova K, Kampe O, Husebye ES, Bensing S, Oksnes M. Residual Corticosteroid Production in Autoimmune Addison Disease. J Clin Endocrinol Metab. 2020 Jul 1;105(7):2430-41. doi: 10.1210/clinem/dgaa256.

Reference Type: DERIVED

PMID: 32392298 (View on PubMed)

Other Identifiers

2018/751/REK sør-øst A (REK)

Identifier Type: -

Identifier Source: org_study_id