Randomized Controlled Trial

. 2014 Sep;171(3):369-77.

doi: 10.1530/EJE-14-0327. Epub 2014 Jun 18.

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

A G Nilsson¹, C Marelli¹, D Fitts¹, R Bergthorsdottir¹, P Burman¹, P Dahlqvist¹, B Ekman¹, B Edén Engström¹, T Olsson¹, O Ragnarsson¹, M Ryberg¹, J Wahlberg¹, H Lennernäs¹, S Skrtic², G Johannsson³

Affiliations

¹ Department of EndocrinologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, SwedenMedical AffairsViroPharma SPRL, Maidenhead, UKBiostatisticsViroPharma IncorporatedDepartment of EndocrinologySkånes University Hospital, SE-205 02 Malmö, SwedenDepartment of Public Health and Clinical MedicineUmeå University, SE-901 87 Umeå, SwedenSection of EndocrinologyDepartment of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, SwedenDepartment of EndocrinologyDiabetes, and Metabolism, University HospitalDepartment of PharmacyUppsala University, SE-751 85 Uppsala, SwedenDepartment of Clinical PharmacologySahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, SwedenAstraZeneca R&DMölndal, Sweden.
² Department of EndocrinologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, SwedenMedical AffairsViroPharma SPRL, Maidenhead, UKBiostatisticsViroPharma IncorporatedDepartment of EndocrinologySkånes University Hospital, SE-205 02 Malmö, SwedenDepartment of Public Health and Clinical MedicineUmeå University, SE-901 87 Umeå, SwedenSection of EndocrinologyDepartment of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, SwedenDepartment of EndocrinologyDiabetes, and Metabolism, University HospitalDepartment of PharmacyUppsala University, SE-751 85 Uppsala, SwedenDepartment of Clinical PharmacologySahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, SwedenAstraZeneca R&DMölndal, SwedenDepartment of EndocrinologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, SwedenMedical AffairsViroPharma SPRL, Maidenhead, UKBiostatisticsViroPharma IncorporatedDepartment of EndocrinologySkånes University Hospital, SE-205 02 Malmö, SwedenDepartment of Public Health and Clinical MedicineUmeå University, SE-901 87 Umeå, SwedenSection of EndocrinologyDepartment of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, SwedenDepartment of EndocrinologyDiabetes, and Metabolism, University HospitalDepartment of PharmacyUppsala University, SE-751 85 Uppsala, SwedenDepartment of Clinical PharmacologySahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, SwedenAstraZeneca R&DMölndal, Sweden.
³ Department of EndocrinologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, SwedenMedical AffairsViroPharma SPRL, Maidenhead, UKBiostatisticsViroPharma IncorporatedDepartment of EndocrinologySkånes University Hospital, SE-205 02 Malmö, SwedenDepartment of Public Health and Clinical MedicineUmeå University, SE-901 87 Umeå, SwedenSection of EndocrinologyDepartment of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, SwedenDepartment of EndocrinologyDiabetes, and Metabolism, University HospitalDepartment of PharmacyUppsala University, SE-751 85 Uppsala, SwedenDepartment of Clinical PharmacologySahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, SwedenAstraZeneca R&DMölndal, Sweden gudmundur.johannsson@gu.se.

PMID: 24944332
PMCID: PMC4106399
DOI: 10.1530/EJE-14-0327

Randomized Controlled Trial

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

A G Nilsson et al. Eur J Endocrinol. 2014 Sep.

. 2014 Sep;171(3):369-77.

doi: 10.1530/EJE-14-0327. Epub 2014 Jun 18.

Authors

Affiliations

¹ Department of EndocrinologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, SwedenMedical AffairsViroPharma SPRL, Maidenhead, UKBiostatisticsViroPharma IncorporatedDepartment of EndocrinologySkånes University Hospital, SE-205 02 Malmö, SwedenDepartment of Public Health and Clinical MedicineUmeå University, SE-901 87 Umeå, SwedenSection of EndocrinologyDepartment of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, SwedenDepartment of EndocrinologyDiabetes, and Metabolism, University HospitalDepartment of PharmacyUppsala University, SE-751 85 Uppsala, SwedenDepartment of Clinical PharmacologySahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, SwedenAstraZeneca R&DMölndal, Sweden.
² Department of EndocrinologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, SwedenMedical AffairsViroPharma SPRL, Maidenhead, UKBiostatisticsViroPharma IncorporatedDepartment of EndocrinologySkånes University Hospital, SE-205 02 Malmö, SwedenDepartment of Public Health and Clinical MedicineUmeå University, SE-901 87 Umeå, SwedenSection of EndocrinologyDepartment of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, SwedenDepartment of EndocrinologyDiabetes, and Metabolism, University HospitalDepartment of PharmacyUppsala University, SE-751 85 Uppsala, SwedenDepartment of Clinical PharmacologySahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, SwedenAstraZeneca R&DMölndal, SwedenDepartment of EndocrinologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, SwedenMedical AffairsViroPharma SPRL, Maidenhead, UKBiostatisticsViroPharma IncorporatedDepartment of EndocrinologySkånes University Hospital, SE-205 02 Malmö, SwedenDepartment of Public Health and Clinical MedicineUmeå University, SE-901 87 Umeå, SwedenSection of EndocrinologyDepartment of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, SwedenDepartment of EndocrinologyDiabetes, and Metabolism, University HospitalDepartment of PharmacyUppsala University, SE-751 85 Uppsala, SwedenDepartment of Clinical PharmacologySahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, SwedenAstraZeneca R&DMölndal, Sweden.
³ Department of EndocrinologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Gothenburg, SwedenMedical AffairsViroPharma SPRL, Maidenhead, UKBiostatisticsViroPharma IncorporatedDepartment of EndocrinologySkånes University Hospital, SE-205 02 Malmö, SwedenDepartment of Public Health and Clinical MedicineUmeå University, SE-901 87 Umeå, SwedenSection of EndocrinologyDepartment of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, SwedenDepartment of EndocrinologyDiabetes, and Metabolism, University HospitalDepartment of PharmacyUppsala University, SE-751 85 Uppsala, SwedenDepartment of Clinical PharmacologySahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, SwedenAstraZeneca R&DMölndal, Sweden gudmundur.johannsson@gu.se.

PMID: 24944332
PMCID: PMC4106399
DOI: 10.1530/EJE-14-0327

Abstract

Objective: The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI).

Design: Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden.

Methods: Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20-40 mg once daily and hydrocortisone 20-40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness).

Results: In stage 1, patients had a median 1.5 (range, 1-9) intercurrent illness events with DR-HC and 1.0 (1-8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1-3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure.

Conclusions: This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

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Figures

**Figure 1**
Patient disposition. DR-HC, dual-release hydrocortisone.

**Figure 2**
(A) Percentage of patients with at least one adverse event (AE) during 3-month intervals of stages 1 and 2. (B) Total number of AEs that occurred during the 1-month run-in period and the first month after randomisation in stage 1, crossover in stage 1 and entry in stage 2 for patients who were initially assigned to dual-release hydrocortisone (DR-HC; n=32) and those who were initially assigned to thrice-daily hydrocortisone (n=32).

**Figure 3**
Percentages of patients with adverse events in quintiles of (A) total (AUC_0–24 h) and (B) afternoon (AUC_6–12 h) cortisol exposure; P>0.05 for comparisons of dual-release hydrocortisone (DR-HC) and thrice-daily hydrocortisone within each quintile. The quintiles for DR-HC were lower than for thrice-daily hydrocortisone as demonstrated by the median (min; max) values for AUC_0–24 h of 3844.7 h×nmol/l (1896.8; 7621.5 h×nmol/l) vs 4672.0 h×nmol/l (2658.3; 7867.2 h×nmol/l) and AUC_6–12 h of 785.1 h×nmol/l (213.4; 2289.4 h×nmol/l) vs 1551.7 h×nmol/l (927.8; 3050.9 h×nmol/l). AUC, area under the curve.

See this image and copyright information in PMC

References

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Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

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Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

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Medical