scholarly journals Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia

2021 ◽  
Author(s):  
Deborah P Merke ◽  
Ashwini Mallappa ◽  
Wiebke Arlt ◽  
Aude Brac de la Perriere ◽  
Angelica Lindén Hirschberg ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Disease Control ◽  
Standard Therapy ◽  
Extension Study ◽  
Modified Release ◽  
Adrenal Hyperplasia ◽  
Androgen Excess ◽  
Phase 3 ◽  
Patient Reported ◽  
17 Hydroxyprogesterone

Abstract Context Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. Objective We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. Results The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months’ extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy). Conclusion MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

Phase 3 and extension study of modified-release hydrocortisone in the treatment of congenital adrenal hyperplasia

2021 ◽  
Author(s):  
Deborah P Merke ◽  
Ashwini Mallappa ◽  
Wiebke Arlt ◽  
La Perriere Aude Brac De ◽  
Angelica Linden Hirschberg ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Extension Study ◽  
Modified Release ◽  
Adrenal Hyperplasia ◽  
Phase 3

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

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Deborah P Merke ◽  
Ashwini Mallappa ◽  
Wiebke Arlt ◽  
Aude Brac de la Perriere ◽  
Angelica Linden Hirschberg ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Disease Control ◽  
Hormonal Control ◽  
Dose Titration ◽  
Modified Release ◽  
Adrenal Hyperplasia ◽  
Diurnal Cortisol ◽  
Classic Cah ◽  
The Mean ◽  
21 Hydroxylase Deficiency

Abstract 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.

scholarly journals Simple Virilization Type of Classic Congenital Adrenal Hyperplasia: Case Report

2018 ◽  
Vol 11 (3) ◽  
pp. 1345-1350
Author(s):  
I Made Pande Dwipayana ◽  
Karismayusa Sudjana ◽  
Siswadi Semadi ◽  
Ketut Suastika ◽  
Made Ratna Saraswati ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Chromosome Analysis ◽  
Ambiguous Genitalia ◽  
Adrenal Hyperplasia ◽  
Laboratory Examination ◽  
Androgen Excess ◽  
Classic Congenital Adrenal Hyperplasia ◽  
Irregular Border ◽  
17 Hydroxyprogesterone ◽  
High Level

We have reported a case of 21 year old patient with congenital adrenal hyperplasia that manifestated with ambiguous genitalia and other signs of androgen excess. Chromosome analysis revealed 46 XX. Laboratory examination and imaging showed high level of 17-hydroxyprogesterone, undeveloped uterus, two ovaries with follicles, no testicles, no prostate, and mass at upper side of both kidney with irregular border confirmed the diagnosis. It was planned to give glucocorticoid therapy to the patient to suppress androgen level, genital reconstruction surgery and psychosexual therapy to reared as a woman, but she refused all suggestions because she wanted to be considered a man.

Radioimmunoassay for 21-deoxycortisol: clinical applications

1985 ◽  
Vol 108 (4) ◽  
pp. 537-544 ◽  
Author(s):  
B. Gueux ◽  
J. Fiet ◽  
M. T. Pham-Huu-Trung ◽  
J. M. Villette ◽  
M. Gourmelen ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Normal Subjects ◽  
Ethyl Acetate Fraction ◽  
Adrenal Hyperplasia ◽  
Acth Stimulation ◽  
Hydroxylase Deficiency ◽  
Androgen Excess ◽  
Heterozygous Carriers ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Abstract. A radioimmunoassay for 21-deoxycortisol is described. The immunogen, 21-deoxycortisol-3-(O-carboxymethyl) oxime-bovine serum albumin, was prepared, the antisera raised against it were studied and the reliability of the assay was checked. The antiserum selected cross-reacted with 11-deoxycortisol (0.08%), corticosterone (0.25%), cortisol (0.6%) and 17-hydroxyprogesterone (1.6%). 21-deoxycortisol was separated by celite partition chromatography and eluted in the 70/30 (v/v) isooctane/ethyl acetate fraction together with 11-deoxycortisol and corticosterone. The radioimmunoassay was used to measure 21-deoxycortisol in the plasma of normal subjects and patients with androgen excess. In normal subjects, men (0.19 ng/ml ± 0.08) and women (0.18 ng/ml ± 0.09) had similar basal levels (mean ± sd). One hour after ACTH stimulation, these levels were increased by a factor of 3.5. In 7 patients treated for classical congenital adrenal hyperplasia associated with 21-hydroxylase deficiency, basal values varied between 9.1 and 39.9 ng/ml (measured at 8 a.m.). In 7 untreated women with lateonset congenital adrenal hyperplasia (with 21-hydroxylase deficiency), ACTH-stimulated levels were increased to between 9 and 25.5 ng/ml. In 14 heterozygous carriers of 21-hydroxylase deficiency, diagnosed by HLA genotyping, all ACTH-stimulated levels were well above the highest corresponding levels in normal subjects, whereas 17-hydroxyprogesterone levels remained within the normal range in 9 of the cases.

scholarly journals A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia

2020 ◽  
Vol 105 (8) ◽  
pp. 2771-2778 ◽  
Author(s):  
Diala El-Maouche ◽  
Deborah P Merke ◽  
Maria G Vogiatzi ◽  
Alice Y Chang ◽  
Adina F Turcu ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Primary Outcome Measure ◽  
Dose Titration ◽  
Adrenal Hyperplasia ◽  
Androgen Excess ◽  
Classic Cah ◽  
17 Hydroxyprogesterone ◽  
And Control ◽  
Dose Levels ◽  
Single Blind

Abstract Context Patients with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic glucocorticoid doses to suppress adrenocorticotropic hormone (ACTH) and control androgen excess. Nevanimibe hydrochloride (ATR-101), which selectively inhibits adrenal cortex function, might reduce androgen excess independent of ACTH and thus allow for lower glucocorticoid dosing in CAH. 17-hydroxyprogesterone (17-OHP) and androstenedione are CAH biomarkers used to monitor androgen excess. Objective Evaluate the efficacy and safety of nevanimibe in subjects with uncontrolled classic CAH. Design This was a multicenter, single-blind, dose-titration study. CAH subjects with baseline 17-OHP ≥4× the upper limit of normal (ULN) received the lowest dose of nevanimibe for 2 weeks followed by a single-blind 2-week placebo washout. Nevanimibe was gradually titrated up if the primary outcome measure (17-OHP ≤2× ULN) was not met. A total of 5 nevanimibe dose levels were possible (125, 250, 500, 750, 1000 mg twice daily). Results The study enrolled 10 adults: 9 completed the study, and 1 discontinued early due to a related serious adverse event. At baseline, the mean age was 30.3 ± 13.8 years, and the maintenance glucocorticoid dose, expressed as hydrocortisone equivalents, was 24.7 ± 10.4 mg/day. Two subjects met the primary endpoint, and 5 others experienced 17-OHP decreases ranging from 27% to 72% during nevanimibe treatment. The most common side effects were gastrointestinal (30%). There were no dose-related trends in adverse events. Conclusions Nevanimibe decreased 17-OHP levels within 2 weeks of treatment. Larger studies of longer duration are needed to further evaluate its efficacy as add-on therapy for CAH.

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