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

Information source: Shire
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Adrenal Insufficiency

Intervention: hydrocortisone (modified release), oral tablet 20 and 5 mg (Drug); Hydrocortisone, oral tablet, 10 mg (Drug)

Phase: Phase 2/Phase 3

Status: Completed

Sponsored by: Shire

Official(s) and/or principal investigator(s):
Maria Forss, MSc BA, Study Director, Affiliation: DuoCort AB
Anna G Nilsson, MD, PhD, Principal Investigator, Affiliation: Sahlgrenska Academy, Gothenburg University

Summary

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

Clinical Details

Official title: A, Randomised, Controlled, Two-armed, Two-period Cross-over, Multi-centre Phase II/III Study to Assess the Safety and Pharmacokinetics of Once-daily Oral Modified-release Hydrocortisone in Patients With Adrenal Insufficiency

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Area Under the Concentration Time Curve From Zero to 24 Hours (AUC0-24h) of Total S-cortisol in Plasma After Multiple Doses During Part A

Secondary outcome:

Maximal Concentration (Cmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Maximal Concentration (Cmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Average Concentration of S-cortisol During the Dosing Interval at Steady State (Css,av) in Plasma After Single and Multiple Dosing During Part A

First Detectable Concentration (Cfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Concentration at 6 Hours (C6h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Concentration at 7 Hours (C7h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Time to Peak Plasma Concentration (Tmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Time to Peak Plasma Concentration (Tmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Time to First Detectable Concentration (Tfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Time to Reach a Concentration of 200 Nanometers (nM) (T200) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Drug Concentration Half-Life From 5 to 24 Hours (t1/2[5-24h]) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Drug Concentration Half-Life From 5 to 14 Hours (t1/2[5-14h]) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A

Area Under the Concentration Time Curve During a Dosing Interval at Steady State (AUCtau) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Area Under the Concentration Time Curve During a Dosing Interval at Steady State Adjusted by Dose (AUCtau/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Area Under the Concentration Time Curve From Zero to 24 Hours Adjusted by Dose (AUC0-24h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Area Under the Concentration Time Curve From Zero to 10 Hours Adjusted by Dose (AUC0-10h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Area Under the Concentration Time Curve From Zero to 4 Hours Adjusted by Dose (AUC0-4h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Average Concentration of S-cortisol During the Dosing Interval at Steady State Adjusted by Dose (Css,av/Dose) in Plasma After Single and Multiple Dosing During Part A

Maximal Concentration Adjusted by Dose (Cmax1/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Time to First Detectable Concentration Adjusted by Dose (Tfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

First Detectable Concentration Adjusted by Dose (Cfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Percentage (%) of Area Under the Concentration Time Curve (AUC) Extrapolation of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Percentage (%) of Fluctuation in Concentrations of S-cortisol at Steady State in Plasma After Single and Multiple Dosing During Part A

Accumulation Ratio (Rac) of S-cortisol in Plasma After Single and Multiple Dosing During Part A

Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A

Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B

Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score Between Once Daily and Thrice Daily Therapy- Part A

Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score - Part B

Comparison of Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score Between Once Daily and Thrice Daily Therapy - Part A

Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score - Part B

Comparison of Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores Between Once Daily and Thrice Daily Therapy- Part A

Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores- Part B

Change From Baseline to 12 Weeks in Diurnal Fatigue Questionnaire for Day Average of Once Daily Therapy - Part A

Change From Baseline to 6 Months in Diurnal Fatigue Questionnaire for Day Average- Part B

Comparison on Participant Compliance Between Once Daily and Thrice Daily Therapy - Part A

Participant Compliance- Part B

Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A

Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Locations and Contacts

Additional Information

Related publications:

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.

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. doi: 10.1517/17425255.4.6.749 . 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. doi: 10.1530/EJE-08-0880. 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.

Starting date: August 2007
Last updated: July 16, 2015

Page last updated: August 23, 2015

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