title: Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.
abstract: OBJECTIVE
  To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI).
  
  
  METHODS
  Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden.
  
  
  METHODS
  Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires.
  
  
  RESULTS
  Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n= 2), gastritis (n= 1) and syncope (n= 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L;P< 0.0001) and HDL cholesterol (0.2 mmol/L;P< 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P= 0.008).
  
  
  CONCLUSIONS
  In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.
authors.affiliation: Department of EndocrinologySahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Nilsson
authors.affiliation: Department of EndocrinologySahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ragnhildur
authors.initials: R
authors.lastname: Bergthorsdottir
authors.affiliation: Department of EndocrinologySkåne University Hospital Malmö, University of Lund, Lund, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Burman
authors.affiliation: Department of Public Health and Clinical MedicineUmeå University, Umeå, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Dahlqvist
authors.affiliation: Departments of Endocrinology and Medical and Health SciencesLinköping University, Linköping, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Ekman
authors.affiliation: Department of Medical SciencesEndocrinology and Metabolism, University Hospital, Uppsala, Sweden.
authors.forename: Britt Edén
authors.initials: BE
authors.lastname: Engström
authors.affiliation: Department of EndocrinologySahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Ragnarsson
authors.affiliation: Department of EndocrinologySahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|AstraZeneca R&DMölndal, Sweden.
authors.forename: Stanko
authors.initials: S
authors.lastname: Skrtic
authors.affiliation: Departments of Endocrinology and Medical and Health SciencesLinköping University, Linköping, Sweden.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wahlberg
authors.affiliation: Shire International GmbHZug, Switzerland.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Achenbach
authors.affiliation: ShireLexington, Massachusetts, USA.
authors.forename: Sharif
authors.initials: S
authors.lastname: Uddin
authors.affiliation: Shire International GmbHZug, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Marelli
authors.affiliation: Department of EndocrinologySahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Johannsson
mesh_terms: D000224:Addison Disease / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D003692:Delayed-Action Preparations; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005759:Gastroenteritis / Q000139:chemically induced; D005938:Glucocorticoids / Q000627:therapeutic use*; D020249:Hormone Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009304:Nasopharyngitis / Q000139:chemically induced; D011788:Quality of Life; D013548:Sweden; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D005938:Glucocorticoids; D006854:Hydrocortisone