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

NCT00915343 | Completed Phase 2 Results

• 3 other identifiers: DC 06/02104-072006-007084-89
• Study Type: interventional
• Target: 64
• Locations: 0 countries
• Sites: N/A

Brief 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

Conditions

Adrenal Insufficiency

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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

  AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The data for combined arm 1+2 after multiple doses were reported.

  Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days

Secondary Outcomes (39)

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

  Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days

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

  Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days

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

  Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days

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

  Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days

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

  Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days

Study Arms (2)

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

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

Interventions

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

Also known as: DuoCort

Novel once daily modified release

Hydrocortisone, oral tablet, 10 mg 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.

Conventional TID hydrocortisone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Shire: lead

Related Publications (14)

• 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.

  PMID: 19383806 BACKGROUND

• 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.

  PMID: 18611115 BACKGROUND

• 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.

  PMID: 1986026 BACKGROUND

• 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.

  PMID: 16895963 BACKGROUND

• 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.

  PMID: 12919163 BACKGROUND

• 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.

  PMID: 6273020 BACKGROUND

• 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.

  PMID: 9156032 BACKGROUND

• 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.

  PMID: 3184107 BACKGROUND

• 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.

  PMID: 19282465 BACKGROUND

• 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.

  PMID: 7889636 BACKGROUND

• 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.

  PMID: 17684047 BACKGROUND

• 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.

  PMID: 16968806 BACKGROUND

• 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.

  PMID: 10997607 BACKGROUND

• 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.

  PMID: 33236103 DERIVED

MeSH Terms

Conditions

Adrenal Insufficiency; Addison Disease

Interventions

Hydrocortisone; Tablets

Condition Hierarchy (Ancestors)

Adrenal Gland Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Study Physician
• Organization: Shire

clinicaltransparency@shire.com

1866-842-5335

Study Officials

• Maria Forss, MSc BA

  DuoCort AB

  STUDY DIRECTOR

• Anna G Nilsson, MD, PhD

  Göteborg University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2009
• First Posted: June 8, 2009
• Study Start: August 21, 2007
• Primary Completion: July 28, 2008
• Study Completion: January 28, 2009
• Last Updated: November 24, 2020
• Results First Posted: July 20, 2015

Record last verified: 2020-11