title: A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia.
abstract: BACKGROUND
  Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm.
  
  
  OBJECTIVE
  The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration.
  
  
  METHODS
  Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology.
  
  
  METHODS
  The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP).
  
  
  RESULTS
  In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs 25.9 ± 7.1 mg/d), with lower 24-hour (P = .004), morning (0700-1500 h; P = .002), and afternoon (1500-2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700-1500 h; P = .02) 17-OHP AUC.
  
  
  CONCLUSIONS
  Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH.
authors.affiliation: National Institutes of Health Clinical Center (A.M., N.S., L.A.D., P.K., C.V.R., D.P.M.), Bethesda, Maryland, USA 20892; Diurnal Ltd (M.J.W., D.D., D.J.A.E., W.A., R.J.R.), Cardiff, United Kingdom CF14 4UJ; The Eunice Kennedy Shriver National Institute of Child Health and Human Development (L.K.N., D.P.M.), Bethesda, Maryland, USA 20892; Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine (W.A.), University of Birmingham, Birmingham, United Kingdom B15 2TT; and University of Sheffield (R.J.R), Sheffield, United Kingdom S10 2RX.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Mallappa
authors.forename: Ninet
authors.initials: N
authors.lastname: Sinaii
authors.forename: Parag
authors.initials: P
authors.lastname: Kumar
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Whitaker
authors.forename: Lori-Ann
authors.initials: LA
authors.lastname: Daley
authors.forename: Dena
authors.initials: D
authors.lastname: Digweed
authors.forename: David J A
authors.initials: DJ
authors.lastname: Eckland
authors.forename: Carol
authors.initials: C
authors.lastname: Van Ryzin
authors.forename: Lynnette K
authors.initials: LK
authors.lastname: Nieman
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ross
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D002214:Capsules; D002940:Circadian Rhythm; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D055815:Young Adult
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D006854:Hydrocortisone