title: Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency.
abstract: OBJECTIVE
  The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI).
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: A G
authors.initials: AG
authors.lastname: Nilsson
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Marelli
authors.affiliation: 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.
authors.forename: D
authors.initials: D
authors.lastname: Fitts
authors.affiliation: 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.
authors.forename: R
authors.initials: R
authors.lastname: Bergthorsdottir
authors.affiliation: 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.
authors.forename: P
authors.initials: P
authors.lastname: Burman
authors.affiliation: 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.
authors.forename: P
authors.initials: P
authors.lastname: Dahlqvist
authors.affiliation: 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.
authors.forename: B
authors.initials: B
authors.lastname: Ekman
authors.affiliation: 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.
authors.forename: B Edén
authors.initials: BE
authors.lastname: Engström
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: Olsson
authors.affiliation: 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.
authors.forename: O
authors.initials: O
authors.lastname: Ragnarsson
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Ryberg
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Wahlberg
authors.affiliation: 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.
authors.forename: H
authors.initials: H
authors.lastname: Lennernäs
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Skrtic
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Johannsson
mesh_terms: D000309:Adrenal Insufficiency / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy*; D000328:Adult; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006261:Headache / Q000139:chemically induced / Q000175:diagnosis; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009304:Nasopharyngitis / Q000139:chemically induced / Q000175:diagnosis; D011446:Prospective Studies
chemical_list: D006854:Hydrocortisone