Biomarker(s) for Glucocorticoids

NCT02152553 | Completed

• 1 other identifier: BIOCORT
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

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).

Conditions

Addison Disease

Keywords

Biomarker; Glucocorticoids; Metabolism; Pharmacology; Metabolomics

Outcome Measures

Primary Outcomes (2)

• Protein profile changes between a state of GC starvation and near physiological GC exposure.

  Using mass spectrometry, protein profile changes in blood, urine and adipose tissue are going to be identified between four points of time during two states: morning and midnight during near physiological GC exposure (sampling 1 and 2), morning and midnight during GC starvation (sampling 3 and 4). Quantitative measurements of all proteins will be used in the bioinformatic analysis. The bioinformatics strategic consists of a stepwise approach based on random forest analysis. Key features in the analysis include finding candidate markers that are increased during normal GC exposure (sampling 1 and 2), reduced during GC starvation (sampling 3 and 4) and exclusion of factors with high variability within normal subjects. Putative biomarkers will go through two levels of internal cross-validation. The investigators would like that this part of the project is not going to be public.

  Changes in proteome (g/dl or umol/l) during 24 hours under two different states of GC exposure.

• Metabolite profile changes between a state of GC starvation and near physiological GC exposure.

  Using mass spectrometry, metabolite profile changes in blood, urine and adipose tissue are going to be identified between four points of time during two states: morning and midnight during near physiological GC exposure (sampling 1 and 2), morning and midnight during GC starvation (sampling 3 and 4). Quantitative measurements of all metabolites will be used in the bioinformatic analysis. The bioinformatics strategic consists of a stepwise approach based on random forest analysis. Key features in the analysis include finding candidate markers that are increased during normal GC exposure (sampling 1 and 2), reduced during GC starvation (sampling 3 and 4) and exclusion of factors with high variability within normal subjects. Putative biomarkers will go through two levels of internal cross-validation. The investigators would like that this part of the project is not going to be public.

  Changes in metabolome (units depending on the kind of metabolome) during 24 hours under two different states of GC exposure.

Secondary Outcomes (1)

• mRNA/miRNA profile changes between a state of GC starvation and near physiological GC exposure.

  Changes in mRNA/miRNA (Svedberg Unit, S) during 24 hours under two different states of GC exposure.

Study Arms (2)

Hydrocortisone

ACTIVE COMPARATOR

Near-physiologic doses of Hydrocortisone are being given to subjects. The first day between 09.00 and 12.00 0,024 mg Hydrocortisone/kg per hour. The first day between 12.00 and 20.00 0,012 mg Hydrocortisone/kg per hour. The first day between 20.00 and 24.00 0,008 mg Hydrocortisone/kg per hour. The second day between 00.00 and 11.00 0,030 mg Hydrocortisone/kg per hour. Hydrocortisone infusion: 0,4 ml Solu Cortef 100 mg (50 mg/ml) added in 999,6 ml sodium chloride 0,9% solution (1 mg Solu Cortef/ 50 ml total solution volume).

Drug: Hydrocortisone

Placebo

PLACEBO COMPARATOR

The same volume of sodium chloride 0,9% as in the other arm where Hydrocortisone is given in saline 0,9% solution. The given volume of sodium chloride will variate chronically as in Hydrocortisone arm.

Drug: Placebo

Interventions

Hydrocortisone DRUG

Also known as: SoluCortef®

Hydrocortisone

Placebo DRUG

Also known as: Sodium chloride 0,9%

Placebo

Eligibility Criteria

• Age: 20 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Vastra Gotaland Region: lead

Study Sites (1)

Sahlgrenska University Hospital

Gothenburg, Västra Götaland County, 413 45, Sweden

Location

Related Publications (2)

• 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.

  PMID: 33821793 RESULT

• 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.

  PMID: 31853550 RESULT

MeSH Terms

Conditions

Addison Disease

Interventions

Hydrocortisone

Condition Hierarchy (Ancestors)

Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Study Officials

• Gudmundur Johannsson, Professor

  Vastra Gotaland Region, Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2014
• First Posted: June 2, 2014
• Study Start: May 1, 2014
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: April 12, 2021

Record last verified: 2021-04

Locations

SE (1)