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

University of Bergen

Status: Active, not recruiting

Conditions: Primary Adrenal Insufficiency

Treatments: Diagnostic Test: Cosyntropin stimulation test; Other: Blood test; Diagnostic Test: Baseline blood tests; Device: 30-hour ambulatory sampling of intestinal fluid

Study type: Interventional

Funder types: Other

Identifiers

NCT03793114

2018/751/REK sør-øst A (REK)

Details and patient eligibility

About

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?

Full 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.

Enrollment: 200 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Screening

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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200 participants in 8 patient groups

Detectable levels of adrenal hormones

Experimental group

Description:

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

Treatment:

Diagnostic Test: Cosyntropin stimulation test

Controls with undetectable hormone levels

Active Comparator group

Description:

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

Treatment:

Diagnostic Test: Cosyntropin stimulation test

Undetectable levels of adrenal hormones

No Intervention group

Description:

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

Congenital adrenal hyperplasia (CAH) control group

Other group

Description:

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

Treatment:

Diagnostic Test: Baseline blood tests

Bilaterally adrenalectomized control group

Other group

Description:

Mapping adrenal steroid profile in patients who are bilaterally adrenalectomized.

Treatment:

Diagnostic Test: Baseline blood tests

Diurnal variation in residual adrenocortical hormone levels

Experimental group

Description:

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.

Treatment:

Device: 30-hour ambulatory sampling of intestinal fluid

Repeated cosyntropin testing in newly diagnosed patients

Experimental group

Description:

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

Treatment:

Diagnostic Test: Cosyntropin stimulation test

Cardiovascular and inflammatory biomarkers

Active Comparator group

Description:

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

Treatment:

Other: Blood test