Comparison of Chronocort® With Standard Glucocorticoid Therapy in Patients With Congenital Adrenal Hyperplasia

NCT02716818 | Completed Phase 3 Results DMC

• 1 other identifier: DIUR-005
• Study Type: interventional
• Target: 122
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a parallel arm, randomised, open-label study, including dose titration and admissions for four overnight stays for 24-hour endocrine profiles. It will compare the efficacy, safety and tolerability of Chronocort® with standard glucocorticoid replacement therapy in the treatment of congenital adrenal hyperplasia (CAH) over a treatment period of 6 months. Dose titration decisions in both treatment groups will be made by a central independent physician, blinded to the treatment arm, using information generated from the 24-hour endocrine profiles. Each treatment arm will be subject to the same titration rules throughout the study, ensuring that opportunities for optimisation and control of androgens are the same in both groups.

Conditions

Congenital Adrenal Hyperplasia

Keywords

Glucocorticoid therapy

Outcome Measures

Primary Outcomes (1)

• Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP

  Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for 17-OHP (17-Hydroxyprogesterone). The primary efficacy variable was the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of 17-OHP. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed 17-OHP values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of 17-OHP when compared to baseline (0).

  24 weeks

Secondary Outcomes (5)

• Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4

  24 weeks

• 17-OHP and A4 by Individual Baseline Treatment Strata.

  24 weeks

• Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit

  24 weeks

• Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass)

  Baseline and 24 weeks

• Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany.

  Baseline and 24 weeks

Study Arms (2)

Chronocort®

EXPERIMENTAL

Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect.

Drug: Chronocort®

standard glucocorticoid therapy

ACTIVE COMPARATOR

Subjects in this arm will continue previous oral glucocorticoid therapy titrated to effect.

Drug: standard glucocorticoid therapy

Interventions

Chronocort® DRUG

Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.

Also known as: Hydrocortisone

Chronocort®

standard glucocorticoid therapy DRUG

Subjects in this arm will continue on their standard hydrocortisone therapy

Also known as: hydrocortisone, prednisone, prednisolone, dexamethasone

standard glucocorticoid therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Known CAH due to 21-hydroxylase deficiency (classic CAH) diagnosed in childhood with documented (at any time) elevated 17-OHP and/or A4 and currently treated with hydrocortisone, prednisone, prednisolone or dexamethasone (or a combination of the aforementioned glucocorticoids) on a stable glucocorticoid therapy for a minimum of 6 months.
• Provision of signed written informed consent.
• Non-pregnant, non-lactating females who are post menopausal, naturally or surgically sterile, or of childbearing potential with a negative urinary pregnancy test and using a medically acceptable method of contraception.
• Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 3 months prior to screening, except in subjects who have been diagnosed with hypertension where the renin is not being used to monitor fludrocortisone replacement.
• Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 3 months prior to screening, except in subjects who have been diagnosed with hypertension where the renin is not being used to monitor fludrocortisone replacement.

You may not qualify if:

• Co-morbid condition requiring daily administration of a medication (or consumption of any material) that interferes with the metabolism of glucocorticoids.
• Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the ULN or elevated liver function tests (ALT or AST \>2 times the ULN).
• Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH.
• Subjects with any other significant medical or psychiatric conditions that in the opinion of the investigator would preclude participation in the trial.
• History of malignancy (other than basal cell carcinoma successfully treated \>6 months prior to entry into the study).
• Subjects with a history of bilateral adrenalectomy.
• Subjects having previously been exposed to Chronocort®.
• Subjects unable to comply with the requirements of the protocol.

Sponsors & Collaborators

• Neurocrine UK Limited: lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892-1932, United States

Location

Related Publications (1)

• Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Linden Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ. Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2063-e2077. doi: 10.1210/clinem/dgab051.

  PMID: 33527139 DERIVED

MeSH Terms

Conditions

Adrenal Hyperplasia, Congenital

Interventions

Hydrocortisone; Prednisone; Prednisolone; Dexamethasone

Condition Hierarchy (Ancestors)

Adrenogenital Syndrome; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Steroid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Gland Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Pregnadienediols; Pregnadienes; Pregnadienetriols; Steroids, Fluorinated

Limitations and Caveats

A limitation of the pre-defined primary endpoint was that it included an unsigned SDS score over a 24-hour period.

Results Point of Contact

• Title: Information Line
• Organization: Diurnal Limited

info@diurnal.co.uk

+44 (0) 2920 682069

Study Officials

• Debbie Merke, MD

  National Institutes of Health (NIH)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2016
• First Posted: March 23, 2016
• Study Start: February 22, 2016
• Primary Completion: July 28, 2018
• Study Completion: July 28, 2018
• Last Updated: May 26, 2021
• Results First Posted: September 4, 2019

Record last verified: 2021-05

Locations

US (1)