Once-Daily Oral Modified-Release Hydrocortisone in Patients With Adrenal Insufficiency - Full Text View

Sponsored by:	DuoCort AB
Information provided by:	DuoCort AB
ClinicalTrials.gov Identifier:	NCT00915343

Purpose

This is a randomised, controlled, open, two-armed, two-period cross-over, multi-centre phase II/III study to assess the safety, tolerability and pharmacokinetics of once-daily oral modified-release hydrocortisone in comparison to conventional thrice-daily oral hydrocortisone tablets in patients with adrenal insufficiency

Condition	Intervention	Phase
Adrenal Insufficiency	Drug: hydrocortisone (modified release), oral tablet 20 and 5 mg Drug: Hydrocortisone, oral tablet, 10 mg	Phase II Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control, Crossover Assignment, Pharmacokinetics/Dynamics Study
Official Title:	A, Randomised, Controlled, Open, Two-Armed, Two-Period Cross-Over, Multi-Centre Phase II/III Study to Assess the Safety, Tolerability and Pharmacokinetics of Once-Daily Oral Modified-Release Hydrocortisone in Comparison to Conventional Thrice-Daily Oral Hydrocortisone Tablets in Patients With Adrenal Insufficiency

Resource links provided by NLM:

Genetics Home Reference related topics: X-linked adrenoleukodystrophy

MedlinePlus related topics: Addison's Disease

Drug Information available for: Hydrocortisone acetate Hydrocortisone Epinephrine bitartrate Epinephrine Proctofoam-HC Hydrocortisone hemisuccinate Hydrocortamate Hydrocortisone 21-sodium succinate Hydrocortisone cypionate Cortisol succinate Cortisol 21-phosphate

U.S. FDA Resources

Further study details as provided by DuoCort AB:

Primary Outcome Measures:

To compare bioavailability between a once-daily modified release hydrocortisone oral tablet and a conventional thrice-daily replacement therapy in patients with chronic primary adrenal insufficiency. [ Time Frame: At randomisation, 1 week and 12 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To compare safety, tolerability and efficacy of the novel modified release formulation to the conventional thrice-daily replacement therapy. [ Time Frame: At randomisation, 4, 8 and 12 weeks ] [ Designated as safety issue: Yes ]
To assess the safety of using the novel modified release formulation as "rescue therapy" during minor intercurrent illnesses in patients with primary adrenal insufficiency. [ Time Frame: At randomisation, 1, 4, 8 and 12 weeks ] [ Designated as safety issue: Yes ]
To assess long-term safety, tolerability and efficacy of the novel modified release formulation during glucocorticoid replacement therapy. [ Time Frame: At randomisation and 12 weeks ] [ Designated as safety issue: Yes ]

Enrollment:	64
Study Start Date:	August 2007
Study Completion Date:	January 2009
Primary Completion Date:	July 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Novel once daily modified release: Experimental Test drug: hydrocortisone (modified release), oral tablet, available as 20 mg and 5 mg. The modified release hydrocortisone tablet was administered orally o.d. at 8 AM in the fasting state	Drug: hydrocortisone (modified release), oral tablet 20 and 5 mg The modified release hydrocortisone tablet was administered orally o.d. at 8 AM in the fasting state. The dose was the same as patients have had before entering the trial
Conventional TID hydrocortisone: Active Comparator Reference drug: hydrocortisone, oral tablet, 10 mg. The reference drug was administered orally thrice daily (at 8 AM, 12 AM and 4 PM)in the same total daily dose as the experimental drug. The morning dose was administered in the fasting state.	Drug: Hydrocortisone, oral tablet, 10 mg The reference drug was administered orally thrice daily (at 8 AM, 12 AM and 4 PM). The morning dose was administered in the fasting state. The total daily dose was the same as in the experimental treatment arm.

Detailed Description:

Adrenal insufficiency 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 replacement therapy with hydrocortisone or cortisone acetate have compromised quality of life, reduced bone mass, increased risk factors for cardiovascular disease 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 newly developed novel dual-, controlled release formulation of hydrocortisone that has in healthy volunteers been able to mimic the circadian pattern of circulating cortisol was studied in patients with primary adrenal insufficiency (Addison's disease).

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Previously diagnosed (e.g. more than 6 months ago) primary 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:

Clinical or laboratory signs of significant cerebral, cardiovascular, respiratory, Hepatobiliary, pancreatic disease
Clinically significant renal dysfunction
Clinical or laboratory signs of significant gastrointestinal emptying or motility disease
Any medication with agents which could interfere with hydrocortisone kinetics
Pregnant or lactating women
Regular dehydroepiandrosterone (DHEA) medication for the past 4 weeks
Oral oestrogen medication for the past 4 weeks
Deranged mineralocorticoid status

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00915343

Sponsors and Collaborators

DuoCort AB

Investigators

Study Director:	Maria Forss, MSc BA	DuoCort AB
Principal Investigator:	Anna G Nilsson, MD, PhD	Sahlgrenska Academy, Gothenburg University

More Information

Publications:

Johannsson G, Bergthorsdottir R, Nilsson A, Lennernas H, Hedner T, Skrtic S. Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol. 2009 Apr 21; [Epub ahead of print]

Lennernäs H, Skrtic S, Johannsson G. Replacement therapy of oral hydrocortisone in adrenal insufficiency: the influence of gastrointestinal factors. Expert Opin Drug Metab Toxicol. 2008 Jun;4(6):749-58. Review.

Esteban NV, Loughlin T, Yergey AL, Zawadzki JK, Booth JD, Winterer JC, Loriaux DL. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab. 1991 Jan;72(1):39-45.

Filipsson H, Monson JP, Koltowska-Häggström M, Mattsson A, Johannsson G. The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab. 2006 Oct;91(10):3954-61. Epub 2006 Aug 8.

Suliman AM, Freaney R, Smith TP, McBrinn Y, Murray B, McKenna TJ. The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency. Clin Endocrinol (Oxf). 2003 Sep;59(3):380-7.

Feek CM, Ratcliffe JG, Seth J, Gray CE, Toft AD, Irvine WJ. Patterns of plasma cortisol and ACTH concentrations in patients with Addison's disease treated with conventional corticosteroid replacement. Clin Endocrinol (Oxf). 1981 May;14(5):451-8.

Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol (Oxf). 1997 Mar;46(3):263-8.

Groves RW, Toms GC, Houghton BJ, Monson JP. Corticosteroid replacement therapy: twice or thrice daily? J R Soc Med. 1988 Sep;81(9):514-6.

Løvås K, Gjesdal CG, Christensen M, Wolff AB, Almås B, Svartberg J, Fougner KJ, Syversen U, Bollerslev J, Falch JA, Hunt PJ, Chatterjee VK, Husebye ES. Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone. Eur J Endocrinol. 2009 Jun;160(6):993-1002. Epub 2009 Mar 12.

al-Shoumer KA, Beshyah SA, Niththyananthan R, Johnston DG. Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults. Clin Endocrinol (Oxf). 1995 Jan;42(1):85-90.

Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M, Decker O, Arlt W, Allolio B. Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. J Clin Endocrinol Metab. 2007 Oct;92(10):3912-22. Epub 2007 Aug 7.

Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients with Addison's disease: a population-based study. J Clin Endocrinol Metab. 2006 Dec;91(12):4849-53. Epub 2006 Sep 12.

Dallman MF, Akana SF, Bhatnagar S, Bell ME, Strack AM. Bottomed out: metabolic significance of the circadian trough in glucocorticoid concentrations. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S40-6. Review.

Responsible Party:	DuoCort AB ( Maria Forss )
Study ID Numbers:	EudraCT: 2006-0007084-89, 104-07
Study First Received:	June 5, 2009
Last Updated:	June 5, 2009
ClinicalTrials.gov Identifier:	NCT00915343 History of Changes
Health Authority:	Europe: European Medicines Agency (EMEA)

Keywords provided by DuoCort AB:

Adrenal insufficiency
Primary adrenal insufficiency
Addison's disease
Hydrocortisone
Modified release

Study placed in the following topic categories:

Anti-Inflammatory Agents
Addison's Disease
Adrenal Insufficiency
Hydrocortisone
Autoimmune Diseases
Adrenal Gland Hypofunction
Cortisol succinate
Adrenal Gland Diseases

Endocrine System Diseases
Hypoadrenalism
X-linked Adrenoleukodystrophy
Adrenoleukodystrophy
Addison Disease
Endocrinopathy
Hydrocortisone acetate
Epinephrine

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Adrenal Insufficiency
Hydrocortisone
Autoimmune Diseases
Cortisol succinate
Immune System Diseases

Therapeutic Uses
Addison Disease
Endocrine System Diseases
Adrenal Gland Diseases
Hydrocortisone acetate
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 03, 2009