Clinical trial NCT02277587: Dual RElease Hydrocortisone Versus conventionAl Glucocorticoid replaceMent Therapy in Hypocortisolism (DREAM)
Official title: A Randomized, Controlled, Multi-Centre Trial on the Effects of Dual-release Hydrocortisone Preparations Versus Conventional Glucocorticoid Replacement Therapy in Patients Affected by Primary and Secondary Adrenal Insufficiency. DREAM Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Primary Adrenal Insufficiency
Secondary Adrenal Insufficiency
Keywords: Plenadren
Addison's disease
Hydrocortisone
Cortisone Acetate
Monocytes
Natural Killer cells
Immunological profile
Inflammation
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2014-10-29
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, controlled, open, three-armed, multi-centre study designed to compare the effects of dual-release hydrocortisone preparations versus conventional glucocorticoid therapy on anthropometric parameters, metabolic syndrome, infectious, immunological profile, cardiovascular system, bone mass and quality of life in patients affected by primary or secondary adrenal insufficiency.

Detailed description: Hypocortisolism is a disease with more than 80% 1-year mortality before the availability of synthetic glucocorticoids. Current replacement therapy has improved this dramatically, but recent data suggest that outcome is still compromised. Patient receiving conventional glucocorticoids therapy have compromised quality of life, reduced bone mass, increased risk factors for cardiovascular disease, infectious, tumors and premature mortality that is more than twice the mortality rate in the background population. Circulating cortisol levels follow a distinct diurnal pattern with high levels in the early morning and low trough values around midnight. Using available formulations for replacement therapy this circadian rhythm is had to mimic and also during the active time of the day high peaks and low troughs occur.

In this trial a dual-release hydrocortisone preparations that has in healthy volunteers been able to mimic the circadian pattern of circulating cortisol was studied in patients with primary and secondary adrenal insufficiency.

Eligibility criteria: Inclusion Criteria:

* Previously diagnosed (e.g. more than 6 months ago) primary or secondary adrenal insufficiency with a stable daily glucocorticoid substitution dose for at least 3 months prior to study entry
* Signed informed consent to participate in the study

Exclusion Criteria:

* acute primary or secondary adrenal insufficiency
* clinical or laboratory signs of significant cerebral, cardiovascular, respiratory, hepatobiliary, pancreatic disease
* clinically significant renal dysfunction
* any medication with agents which could interfere with glucocorticoid kinetics

Primary outcomes:
measure: Change from baseline in measurement of weight at 3 and 6 months
timeFrame: 0, + 3 months, + 6 months
Secondary outcomes:
measure: Change from baseline in metabolic status at 3 and 6 months
timeFrame: 0, + 3 months, + 6 months
measure: Evaluation of immunological profile at baseline 3 and 6 months.
timeFrame: 0, + 3 months, + 6 months
measure: Evaluation of bone deposition and resorption markers from baseline at 6 months
timeFrame: 0, + 6 months
measure: Evaluation of epicardial fat thickness from baseline at 6 months
timeFrame: 0, + 6 months
measure: Evaluation of hepatic steatosis from baseline at 6 months
timeFrame: 0, + 6 months
measure: Changes in quality of life from baseline at 2, 3 and 6 months
timeFrame: 0, + 2 months, +3 months, + 6 months
measure: Bone mineral density
timeFrame: 0, + 6 months
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Department of Experimental Medicine
Study officials:
affiliation: Dept. Experimental Medicine
name: Andrea M Isidori, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nilsson AG, Marelli C, Fitts D, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engstrom BE, Olsson T, Ragnarsson O, Ryberg M, Wahlberg J, Lennernas H, Skrtic S, Johannsson G. Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency. Eur J Endocrinol. 2014 Sep;171(3):369-77. doi: 10.1530/EJE-14-0327. Epub 2014 Jun 18.
citation: Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engstrom BE, Olsson T, Ragnarsson O, Ryberg M, Wahlberg J, Biller BM, Monson JP, Stewart PM, Lennernas H, Skrtic S. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab. 2012 Feb;97(2):473-81. doi: 10.1210/jc.2011-1926. Epub 2011 Nov 23.
citation: Johannsson G, Bergthorsdottir R, Nilsson AG, Lennernas H, Hedner T, Skrtic S. Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol. 2009 Jul;161(1):119-30. doi: 10.1530/EJE-09-0170. Epub 2009 Apr 21.
citation: Venneri MA, Hasenmajer V, Fiore D, Sbardella E, Pofi R, Graziadio C, Gianfrilli D, Pivonello C, Negri M, Naro F, Grossman AB, Lenzi A, Pivonello R, Isidori AM. Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2998-3009. doi: 10.1210/jc.2018-00346.
citation: Isidori AM, Venneri MA, Graziadio C, Simeoli C, Fiore D, Hasenmajer V, Sbardella E, Gianfrilli D, Pozza C, Pasqualetti P, Morrone S, Santoni A, Naro F, Colao A, Pivonello R, Lenzi A. Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2018 Mar;6(3):173-185. doi: 10.1016/S2213-8587(17)30398-4. Epub 2017 Dec 8.