Clinical trial NCT03793114: Screening and Stimulation Testing for Residual Secretion of Adrenal Steroid Hormones in Autoimmune Addison's Disease
Official title: Residual Secretion of Adrenal Steroid Hormones in Addison's Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Primary Adrenal Insufficiency
Lead sponsor: University of Bergen
Sponsor class: OTHER
Collaborators: name: Karolinska Institutet
name: Charite University, Berlin, Germany
First posted: 2019-01-04
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

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.

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.

Primary outcomes:
measure: The percentage of included patients with residual secretion of cortisol and aldosterone.
timeFrame: 1 day
Secondary outcomes:
measure: Medication-fasting adrenocorticotropic hormone (ACTH)-stimulated levels of metanephrines
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol precursors
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol precursors
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol precursors
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol metabolites
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol metabolites
timeFrame: 1 day
measure: Medication-fasting basal levels of cortisol metabolites
timeFrame: 1 day
measure: Medication-fasting basal levels of aldosterone
timeFrame: 1 day
measure: Medication-fasting basal levels of aldosterone
timeFrame: 1 day
measure: Medication-fasting basal levels of aldosterone precursors
timeFrame: 1 day
measure: Medication-fasting basal levels of aldosterone precursors
timeFrame: 1 day
measure: Medication-fasting basal levels of aldosterone metabolites
timeFrame: 1 day
measure: Medication-fasting basal levels of aldosterone metabolites
timeFrame: 1 day
measure: Medication-fasting basal levels of renin in patients with and without residual function.
timeFrame: 1 day
measure: Medication-fasting basal levels of renin in patients with and without residual function.
timeFrame: 1 day
measure: Medication-fasting basal levels of ACTH in patients with and without residual function.
timeFrame: 1 day
measure: Medication-fasting basal levels of ACTH in patients with and without residual function.
timeFrame: 1 day
measure: Medication-fasting basal levels of metanephrines in patients with and without residual function
timeFrame: 1 day
measure: Medication-fasting basal levels of metanephrines in patients with and without residual function
timeFrame: 1 day
measure: Medication-fasting ACTH-stimulated levels of cortisol
timeFrame: 1 day
measure: Medication-fasting ACTH-stimulated levels of cortisol precursors
timeFrame: 1 day
measure: Medication-fasting ACTH-stimulated levels of cortisol metabolites
timeFrame: 1 day
measure: Medication-fasting ACTH-stimulated levels of aldosterone
timeFrame: 1 day
measure: Medication-fasting ACTH-stimulated levels of aldosterone precursors
timeFrame: 1 day
measure: Medication-fasting ACTH-stimulated levels of aldosterone metabolites
timeFrame: 1 day
measure: Cortisol replacement doses, including stress doses in patients with and without residual function.
timeFrame: 1 day
measure: Cortisol stress doses in patients with and without residual function.
timeFrame: 1 day
measure: Fludrocortisone replacement doses in patients with and without residual function.
timeFrame: 1 day
measure: In patients with and without residual function: disease-specific quality-of-life
timeFrame: 1 day
measure: In patients with and without residual function, generic health-related quality of life by the Short Form (36) Health Survey
timeFrame: 1 day
measure: Number of adrenal crises pr. 100 patient years
timeFrame: 1 day
Other outcomes:
measure: Adrenocortical hormones in congenital adrenal hyperplasia (CAH) controls
timeFrame: 1 day
measure: Adrenocortical hormones in bilaterally adrenalectomized controls
timeFrame: 1 day
measure: Change in response to cosyntropin testing
timeFrame: 4 days
measure: Diurnal variation in adrenocortical hormone secretion
timeFrame: 2 days
Locations:
city: Berlin
country: Germany
facility: Endokrinologie in Charlottenburg
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Stockholm
country: Sweden
facility: Karolinska Institutet
Study officials:
affiliation: University of Bergen
name: Eystein S Husebye, M.D, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.