Once-daily Oral Modified Release Hydrocortisone in Patients With Adrenal Insufficiency

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

64 participants

Study Classification

INTERVENTIONAL

Study Start Date

2007-08-21

Study Completion Date

2009-01-28

Brief Summary

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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

Detailed Description

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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).

Conditions

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Adrenal Insufficiency

Keywords

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Novel once daily modified release

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

Group Type EXPERIMENTAL

hydrocortisone (modified release), oral tablet 20 and 5 mg

Intervention Type DRUG

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

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.

Group Type ACTIVE_COMPARATOR

Hydrocortisone, oral tablet, 10 mg

Intervention Type DRUG

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.

Interventions

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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

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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DuoCort

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Maria Forss, MSc BA

Role: STUDY_DIRECTOR

DuoCort AB

Anna G Nilsson, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Göteborg University

References

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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.

Reference Type BACKGROUND

PMID: 19383806 (View on PubMed)

Lennernas 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. doi: 10.1517/17425255.4.6.749.

Reference Type BACKGROUND

PMID: 18611115 (View on PubMed)

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. doi: 10.1210/jcem-72-1-39.

Reference Type BACKGROUND

PMID: 1986026 (View on PubMed)

Filipsson H, Monson JP, Koltowska-Haggstrom 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. doi: 10.1210/jc.2006-0524. Epub 2006 Aug 8.

Reference Type BACKGROUND

PMID: 16895963 (View on PubMed)

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. doi: 10.1046/j.1365-2265.2003.01860.x.

Reference Type BACKGROUND

PMID: 12919163 (View on PubMed)

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. doi: 10.1111/j.1365-2265.1981.tb00634.x.

Reference Type BACKGROUND

PMID: 6273020 (View on PubMed)

Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol (Oxf). 1997 Mar;46(3):263-8. doi: 10.1046/j.1365-2265.1997.1340955.x.

Reference Type BACKGROUND

PMID: 9156032 (View on PubMed)

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. doi: 10.1177/014107688808100906.

Reference Type BACKGROUND

PMID: 3184107 (View on PubMed)

Lovas K, Gjesdal CG, Christensen M, Wolff AB, Almas 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. doi: 10.1530/EJE-08-0880. Epub 2009 Mar 12.

Reference Type BACKGROUND

PMID: 19282465 (View on PubMed)

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. doi: 10.1111/j.1365-2265.1995.tb02602.x.

Reference Type BACKGROUND

PMID: 7889636 (View on PubMed)

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. doi: 10.1210/jc.2007-0685. Epub 2007 Aug 7.

Reference Type BACKGROUND

PMID: 17684047 (View on PubMed)

Bergthorsdottir R, Leonsson-Zachrisson M, Oden 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. doi: 10.1210/jc.2006-0076. Epub 2006 Sep 12.

Reference Type BACKGROUND

PMID: 16968806 (View on PubMed)

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. doi: 10.1038/sj.ijo.0801276.

Reference Type BACKGROUND

PMID: 10997607 (View on PubMed)

Espiard S, McQueen J, Sherlock M, Ragnarsson O, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engstrom BE, Skrtic S, Wahlberg J, Stewart PM, Johannsson G. Improved Urinary Cortisol Metabolome in Addison Disease: A Prospective Trial of Dual-Release Hydrocortisone. J Clin Endocrinol Metab. 2021 Mar 8;106(3):814-825. doi: 10.1210/clinem/dgaa862.

Reference Type DERIVED

PMID: 33236103 (View on PubMed)

Other Identifiers

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104-07

Identifier Type: -

Identifier Source: secondary_id

2006-007084-89

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

DC 06/02

Identifier Type: -

Identifier Source: org_study_id

Once-daily Oral Modified Release Hydrocortisone in Patients With Adrenal Insufficiency

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Keywords

Study Design

Study Groups

Novel once daily modified release

hydrocortisone (modified release), oral tablet 20 and 5 mg

Conventional TID hydrocortisone

Hydrocortisone, oral tablet, 10 mg

Interventions

hydrocortisone (modified release), oral tablet 20 and 5 mg

Hydrocortisone, oral tablet, 10 mg

Other Intervention Names

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Sponsors

Shire

Responsible Party

Principal Investigators

Maria Forss, MSc BA

Anna G Nilsson, MD, PhD

References

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.

Lennernas 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. doi: 10.1517/17425255.4.6.749.

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. doi: 10.1210/jcem-72-1-39.

Filipsson H, Monson JP, Koltowska-Haggstrom 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. doi: 10.1210/jc.2006-0524. 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. doi: 10.1046/j.1365-2265.2003.01860.x.

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. doi: 10.1111/j.1365-2265.1981.tb00634.x.

Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol (Oxf). 1997 Mar;46(3):263-8. doi: 10.1046/j.1365-2265.1997.1340955.x.

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. doi: 10.1177/014107688808100906.

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. doi: 10.1111/j.1365-2265.1995.tb02602.x.

Bergthorsdottir R, Leonsson-Zachrisson M, Oden 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. doi: 10.1210/jc.2006-0076. 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. doi: 10.1038/sj.ijo.0801276.

Other Identifiers

104-07

2006-007084-89

DC 06/02