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OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia

Background: Patients with congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency have poor health outcomes related to inadequate glucocorticoid (GC) replacement. We compared disease control of adults with classic CAH treated with a modified release hydrocortisone (MRHC), which...

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Autores principales: Merke, Deborah P, Mallappa, Ashwini, Arlt, Wiebke, de la Perriere, Aude Brac, Hirschberg, Angelica Linden, Juul, Anders, Newell-Price, John D C, Perry, Colin Graham, Prete, Alessandro, Rees, Aled, Reisch, Nicole, Stikkelbroeck, Monica, Touraine, Philippe A, Maltby, Kerry, Treasure, Peter, Porter, John, Ross, Richard John M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209435/
http://dx.doi.org/10.1210/jendso/bvaa046.214
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author Merke, Deborah P
Mallappa, Ashwini
Arlt, Wiebke
de la Perriere, Aude Brac
Hirschberg, Angelica Linden
Juul, Anders
Newell-Price, John D C
Perry, Colin Graham
Prete, Alessandro
Rees, Aled
Reisch, Nicole
Stikkelbroeck, Monica
Touraine, Philippe A
Maltby, Kerry
Treasure, Peter
Porter, John
Ross, Richard John M
author_facet Merke, Deborah P
Mallappa, Ashwini
Arlt, Wiebke
de la Perriere, Aude Brac
Hirschberg, Angelica Linden
Juul, Anders
Newell-Price, John D C
Perry, Colin Graham
Prete, Alessandro
Rees, Aled
Reisch, Nicole
Stikkelbroeck, Monica
Touraine, Philippe A
Maltby, Kerry
Treasure, Peter
Porter, John
Ross, Richard John M
author_sort Merke, Deborah P
collection PubMed
description Background: Patients with congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency have poor health outcomes related to inadequate glucocorticoid (GC) replacement. We compared disease control of adults with classic CAH treated with a modified release hydrocortisone (MRHC), which replicates physiological diurnal cortisol secretion, versus standard GC therapy. Methods: 6 month, open label, study in 122 patients randomised either to treatment with MRHC (Chronocort®, Diurnal Ltd, Cardiff, UK) twice daily at ~ 0700h & ~2300h, or to remain on their standard GC regimen (hydrocortisone, prednisolone, prednisone, dexamethasone). Patients had 24-hr profiling of serum 17-hydroxyprogesterone (17-OHP) at baseline and for dose titration at 4 and 12 weeks. The primary efficacy endpoint was the change from baseline to 24 weeks in the natural logarithm of the mean of the 24-hr standard deviation score (SDS) profile for 17-OHP. Results: Both groups achieved improved hormonal control at 24 weeks. The mean 24-hour 17-OHP SDS was significantly lower on MRHC compared to standard GC at 4 weeks (p = 0.0074) and 12 weeks (p = 0.019), but not at 24 weeks. In post-hoc analyses at 24 weeks, MRHC treatment showed a greater reduction in 17-OHP SDS compared to standard GC in the morning, 0700-1500h (p = 0.0442) and a greater reduction in log transformed 17-OHP 24 hour AUC (p=0.0251). Defining a morning 17-OHP <1200ng/dl (<36 nmol/L) as good control, for patients not controlled at baseline 85% were well controlled at 24 weeks with MHRC versus 50% on standard GC. For patients controlled at baseline 100% were controlled at 24 weeks on MHRC versus 84% with standard GC (p = 0.0018). The variability of 17-OHP over 24 hours was significantly reduced in the MRHC group compared to standard GC: the ratio of amplitude at 24 weeks divided by amplitude at baseline was for MRHC, 0.361 [95% CI: 0.235, 0.651], and standard GC, 0.917 [0.773, 1.366]; (p = 0.0001).There were no adrenal crises on MRHC and fewer stress doses despite similar incidence of inter-current illness to the standard GC group which had 3 adrenal crises. MRHC was associated with patient reported benefit including restoration of menstruation in 4 patients on MRHC and 1 on standard GC and two partner pregnancies in patients on MRHC and none on standard GC. Discussion: This is the largest randomised controlled trial of GC treatment in CAH and showed that intensification of therapy could improve control of the androgen-precursor, 17-OHP, and that this hormonal control was superior in the morning with MRHC. MRHC reduced the fluctuations in 17-OHP such that in the majority of patients the 17-OHP profile was within the reference range throughout 24 hours, providing consistent and optimal disease control. Conclusion: Diurnal cortisol replacement with a MRHC improves the biochemical control of classic CAH with a twice-daily therapeutic regimen.
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spelling pubmed-72094352020-05-13 OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia Merke, Deborah P Mallappa, Ashwini Arlt, Wiebke de la Perriere, Aude Brac Hirschberg, Angelica Linden Juul, Anders Newell-Price, John D C Perry, Colin Graham Prete, Alessandro Rees, Aled Reisch, Nicole Stikkelbroeck, Monica Touraine, Philippe A Maltby, Kerry Treasure, Peter Porter, John Ross, Richard John M J Endocr Soc Adrenal Background: Patients with congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency have poor health outcomes related to inadequate glucocorticoid (GC) replacement. We compared disease control of adults with classic CAH treated with a modified release hydrocortisone (MRHC), which replicates physiological diurnal cortisol secretion, versus standard GC therapy. Methods: 6 month, open label, study in 122 patients randomised either to treatment with MRHC (Chronocort®, Diurnal Ltd, Cardiff, UK) twice daily at ~ 0700h & ~2300h, or to remain on their standard GC regimen (hydrocortisone, prednisolone, prednisone, dexamethasone). Patients had 24-hr profiling of serum 17-hydroxyprogesterone (17-OHP) at baseline and for dose titration at 4 and 12 weeks. The primary efficacy endpoint was the change from baseline to 24 weeks in the natural logarithm of the mean of the 24-hr standard deviation score (SDS) profile for 17-OHP. Results: Both groups achieved improved hormonal control at 24 weeks. The mean 24-hour 17-OHP SDS was significantly lower on MRHC compared to standard GC at 4 weeks (p = 0.0074) and 12 weeks (p = 0.019), but not at 24 weeks. In post-hoc analyses at 24 weeks, MRHC treatment showed a greater reduction in 17-OHP SDS compared to standard GC in the morning, 0700-1500h (p = 0.0442) and a greater reduction in log transformed 17-OHP 24 hour AUC (p=0.0251). Defining a morning 17-OHP <1200ng/dl (<36 nmol/L) as good control, for patients not controlled at baseline 85% were well controlled at 24 weeks with MHRC versus 50% on standard GC. For patients controlled at baseline 100% were controlled at 24 weeks on MHRC versus 84% with standard GC (p = 0.0018). The variability of 17-OHP over 24 hours was significantly reduced in the MRHC group compared to standard GC: the ratio of amplitude at 24 weeks divided by amplitude at baseline was for MRHC, 0.361 [95% CI: 0.235, 0.651], and standard GC, 0.917 [0.773, 1.366]; (p = 0.0001).There were no adrenal crises on MRHC and fewer stress doses despite similar incidence of inter-current illness to the standard GC group which had 3 adrenal crises. MRHC was associated with patient reported benefit including restoration of menstruation in 4 patients on MRHC and 1 on standard GC and two partner pregnancies in patients on MRHC and none on standard GC. Discussion: This is the largest randomised controlled trial of GC treatment in CAH and showed that intensification of therapy could improve control of the androgen-precursor, 17-OHP, and that this hormonal control was superior in the morning with MRHC. MRHC reduced the fluctuations in 17-OHP such that in the majority of patients the 17-OHP profile was within the reference range throughout 24 hours, providing consistent and optimal disease control. Conclusion: Diurnal cortisol replacement with a MRHC improves the biochemical control of classic CAH with a twice-daily therapeutic regimen. Oxford University Press 2020-05-08 /pmc/articles/PMC7209435/ http://dx.doi.org/10.1210/jendso/bvaa046.214 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Adrenal
Merke, Deborah P
Mallappa, Ashwini
Arlt, Wiebke
de la Perriere, Aude Brac
Hirschberg, Angelica Linden
Juul, Anders
Newell-Price, John D C
Perry, Colin Graham
Prete, Alessandro
Rees, Aled
Reisch, Nicole
Stikkelbroeck, Monica
Touraine, Philippe A
Maltby, Kerry
Treasure, Peter
Porter, John
Ross, Richard John M
OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia
title OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia
title_full OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia
title_fullStr OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia
title_full_unstemmed OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia
title_short OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia
title_sort or25-02 a phase 3 study of a modified-release hydrocortisone in the treatment of congenital adrenal hyperplasia
topic Adrenal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209435/
http://dx.doi.org/10.1210/jendso/bvaa046.214
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