Clinical trial NCT02152553: Biomarker(s) for Glucocorticoids
Official title: Protein/Metabolite Biomarker(s) for Glucocorticoid Action; an Experimental Trial in Patients With Adrenal Insufficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Addison Disease
Keywords: Biomarker
Glucocorticoids
Metabolism
Pharmacology
Metabolomics
Lead sponsor: Vastra Gotaland Region
Sponsor class: OTHER_GOV
First posted: 2014-06-02
Enrollment: 11
Sex: ALL
Minimum age (years): 20
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The investigators have shown that patients with adrenal insufficiency (Addison's disease), a rare disorder, have doubled the expected mortality rate in Sweden despite Standard of Care glucocorticoid (GC) replacement. One % of the Swedish population are, however, receiving GCs for inflammatory diseases, but management is empirical and adjusted to underlying disease activity. The desired anti-inflammatory therapeutic effects cannot be differentiated from the adverse metabolic (osteoporosis, obesity, diabetes mellitus) and immunosuppressive side effects of GC. This frequently results in suboptimal GC therapy with adverse effects due to over-dosing or poor efficacy due to under-dosing. The primary aim is to identify a biomarker for the metabolic effects of GCs. Patients with Addison's disease completely lack endogenous GCs and can therefore be considered a human GC knock-out model. They can therefore be studied during near-physiological exposure and during GC starvation. This will uniquely allow a very clean biomarker identification model (using transcriptomics, proteomics and metabolomics). The secondary aim is to validate candidate biomarker(s) in a dose-response study using the same patient population. A biomarker of GC actions will make it possible to individualised therapy during pharmacological GC treatment. It would allow GC replacement to be monitored in Addison's disease and could become a specific diagnostic tool in patients with GC deficiency and excess (Cushings syndrome).


Eligibility criteria: Inclusion Criteria:

* Primary adrenal insufficiency under stable glucocorticoid replacement therapy (15-30 mg of Hydrocortisone stable dose the last 3 months) due to autoimmune adrenalitis (disease diagnosed at least 12 months before inclusion), age 20-60 years, BMI 20-30 kg/m2, and ability to comply with the protocol procedures.

Exclusion Criteria:

* Glucocorticoid replacement therapy for indication other than primary adrenal treatment, any treatment with sex hormones inclusive contraceptive drugs, treatment with levothyroxine, diabetes mellitus, renal or liver failure, significant and symptomatic cardiovascular disease.

Primary outcomes:
measure: Protein profile changes between a state of GC starvation and near physiological GC exposure.
timeFrame: Changes in proteome (g/dl or umol/l) during 24 hours under two different states of GC exposure.
measure: Metabolite profile changes between a state of GC starvation and near physiological GC exposure.
timeFrame: Changes in metabolome (units depending on the kind of metabolome) during 24 hours under two different states of GC exposure.
Secondary outcomes:
measure: mRNA/miRNA profile changes between a state of GC starvation and near physiological GC exposure.
timeFrame: Changes in mRNA/miRNA (Svedberg Unit, S) during 24 hours under two different states of GC exposure.
Other outcomes:
Locations:
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
state: Vastra Gotaland Region
Study officials:
affiliation: Vastra Gotaland Region, Sahlgrenska University Hospital
name: Gudmundur Johannsson, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chantzichristos D, Svensson PA, Garner T, Glad CA, Walker BR, Bergthorsdottir R, Ragnarsson O, Trimpou P, Stimson RH, Borresen SW, Feldt-Rasmussen U, Jansson PA, Skrtic S, Stevens A, Johannsson G. Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial. Elife. 2021 Apr 6;10:e62236. doi: 10.7554/eLife.62236.
citation: Melvin A, Chantzichristos D, Kyle CJ, Mackenzie SD, Walker BR, Johannsson G, Stimson RH, O'Rahilly S. GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement. J Clin Endocrinol Metab. 2020 May 1;105(5):1427-34. doi: 10.1210/clinem/dgz277.