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, 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

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.

© 2014 The authors.

Figures

Figure 1
Figure 1
Patient disposition. DR-HC, dual-release hydrocortisone.
Figure 2
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
Figure 3
Percentages of patients with adverse events in quintiles of (A) total (AUC0–24 h) and (B) afternoon (AUC6–12 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 AUC0–24 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 AUC6–12 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.

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Source: PubMed

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