Dual RElease Hydrocortisone Versus conventionAl Glucocorticoid replaceMent Therapy in Hypocortisolism (DREAM) (DREAM)

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ClinicalTrials.gov Identifier: NCT02277587

Recruitment Status : Completed

First Posted : October 29, 2014

Last Update Posted : April 25, 2019

Sponsor:

Information provided by (Responsible Party):

Andrea M. Isidori, University of Roma La Sapienza

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Primary Adrenal Insufficiency Secondary Adrenal Insufficiency	Drug: Plenadren Drug: Conventional glucocorticoid therapy	Phase 4

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	89 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Single (Outcomes Assessor)
Primary Purpose:	Treatment
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.
Actual Study Start Date :	March 2014
Actual Primary Completion Date :	June 2016
Actual Study Completion Date :	June 2016

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Autoimmune Addison disease Familial glucocorticoid deficiency

MedlinePlus related topics: Addison Disease Steroids

Drug Information available for: Hydrocortisone acetate Hydrocortisone Hydrocortisone sodium succinate Hydrocortisone cypionate Hydrocortisone valerate Hydrocortisone probutate Proctofoam-HC

Genetic and Rare Diseases Information Center resources: Secondary Adrenal Insufficiency Addison's Disease

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Plenadren Plenadren (modified release hydrocortison) 20-25 or 30 mg oral tablets will be administered once-daily at 8.00 AM in the fasting state The dose is kept the same as patients had before entering the trial.	Drug: Plenadren Oral Tablets: 20-25-30 mg Other Name: Dual-release Hydrocortisone
Active Comparator: Conventional glucocorticoid therapy Hydrocortisone (dose range 10 to 30) mg will be continued as before entering the study. Cortisone Acetate (dose 25 to 37.5 mg) will be continued as before entering the study. The morning dose will be administered in the fasting state. The total daily dose and timing is not changed during the study period.	Drug: Conventional glucocorticoid therapy Oral Tablets: 20-25-30- 37.5 mg Other Name: Hydrocortisone / Cortisone Acetate
No Intervention: Healthy volunteers Healthy volunteers will be enrolled as control group

Outcome Measures

Primary Outcome Measures :

Change from baseline in measurement of weight at 3 and 6 months [ Time Frame: 0, + 3 months, + 6 months ]
Single outcome measurement of body weight (kg).

Secondary Outcome Measures :

Change from baseline in metabolic status at 3 and 6 months [ Time Frame: 0, + 3 months, + 6 months ]
Composite outcome measure consisting of simultaneous measurment of: Glycaemia, Insulinemia, Homa index, Glycated Haemoglobin, Total Cholesterol, LDL cholesterol, HDL cholesterol, Triglyceredes; the composite outcome measured at 3 and 6 months.
Evaluation of immunological profile at baseline 3 and 6 months. [ Time Frame: 0, + 3 months, + 6 months ]
Composite outcome measure consisting of simultaneous measurment of: Full Count Blood Cell, ESR, Fibrinogen, Immunoglobulin, PCR; measured at baseline, 3 and 6 months.
Evaluation of bone deposition and resorption markers from baseline at 6 months [ Time Frame: 0, + 6 months ]
Composite outcome measure consisting of simultaneous measurment of: serum calcium, phosphate, parathyroid hormone (PTH), 25OH-vitamin D, phosphate, osteocalcin, bone phosphate alkaline (sBALP), serum-cross-linked N and C-telopeptide of bone type I collagen (NTx- CTx); measure at baseline and 6 months.
Evaluation of epicardial fat thickness from baseline at 6 months [ Time Frame: 0, + 6 months ]
Measurement of epicardial fat thickness (EFT) by hihg-resolution M-B-mode transthoracic echocardiography from baseline at 6 months.
Evaluation of hepatic steatosis from baseline at 6 months [ Time Frame: 0, + 6 months ]
Evaluation of hepatic steatosis by conventional ultrasound of the liver and with ASQ software with dedicated equipment and 7-5 Mhz convex probe frome baseline at 6 months.
Changes in quality of life from baseline at 2, 3 and 6 months [ Time Frame: 0, + 2 months, +3 months, + 6 months ]
Quality of life will be measured by questionnaires: AddiQol, Middle Sex Hospital Questionnaire (MHQ), International Index of Erectile Function (IIEF), Female Sexual Function Index (FSFI), Beck Depression Inventory Test (BDI-II).
Bone mineral density [ Time Frame: 0, + 6 months ]
Bone mineral density quantified by Dual X-Ray Absorptiometry (DEXA)

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02277587

Locations

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Italy
Department of Experimental Medicine
Rome, Italy, 00161

Sponsors and Collaborators

University of Roma La Sapienza

Investigators

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Principal Investigator:	Andrea M Isidori, MD, PhD	Dept. Experimental Medicine

More Information

Publications of Results:

Nilsson AG, Marelli C, Fitts D, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engström BE, Olsson T, Ragnarsson O, Ryberg M, Wahlberg J, Lennernäs 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.

Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engström BE, Olsson T, Ragnarsson O, Ryberg M, Wahlberg J, Biller BM, Monson JP, Stewart PM, Lennernäs 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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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Responsible Party:	Andrea M. Isidori, Professor, University of Roma La Sapienza
ClinicalTrials.gov Identifier:	NCT02277587
Other Study ID Numbers:	Hyposurrenalism_1
First Posted:	October 29, 2014 Key Record Dates
Last Update Posted:	April 25, 2019
Last Verified:	April 2019

Keywords provided by Andrea M. Isidori, University of Roma La Sapienza:


Plenadren Addison's disease Hydrocortisone Cortisone Acetate	Monocytes Natural Killer cells Immunological profile Inflammation

Additional relevant MeSH terms:

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Neoplasm Metastasis Adrenal Insufficiency Addison Disease Neoplastic Processes Neoplasms Pathologic Processes Adrenal Gland Diseases Endocrine System Diseases Autoimmune Diseases Immune System Diseases	Hydrocortisone Hydrocortisone 17-butyrate 21-propionate Hydrocortisone acetate Hydrocortisone hemisuccinate Cortisone Glucocorticoids Anti-Inflammatory Agents Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs

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