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

A G Nilsson; C Marelli; D Fitts; R Bergthorsdottir; P Burman; P Dahlqvist; B Ekman; B Edén Engström; T Olsson; O Ragnarsson; M Ryberg; J Wahlberg; H Lennernäs; S Skrtic; G Johannsson

doi:10.1530/EJE-14-0327

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

Eur J Endocrinol. 2014 Sep;171(3):369-77. doi: 10.1530/EJE-14-0327. Epub 2014 Jun 18.

Authors

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.

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.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adrenal Insufficiency / blood
Adrenal Insufficiency / diagnosis*
Adrenal Insufficiency / drug therapy*
Adult
Cross-Over Studies
Drug Administration Schedule
Female
Follow-Up Studies
Headache / chemically induced
Headache / diagnosis
Humans
Hydrocortisone / administration & dosage*
Hydrocortisone / adverse effects*
Male
Middle Aged
Nasopharyngitis / chemically induced
Nasopharyngitis / diagnosis
Prospective Studies

Substances

Hydrocortisone