Pilot Study to Characterize and Examine the Pharmacokinetics and Efficacy of Chronocort® in Adults With CAH

A Phase 2 Pilot Study to Characterize and Examine the Pharmacokinetics and Disease Bio-marker Response of Chronocort® in Adults With Congenital Adrenal Hyperplasia

The purpose of this study is to gather safety and effectiveness information about a new formulation of Hydrocortisone (Chronocort®) used to treat patients with a disease called congenital adrenal hyperplasia (CAH). Hydrocortisone is the man-made version of the hormone cortisol, which is released in the body following a regular daily pattern. The objective of the study is to measure the levels of hydrocortisone that are absorbed into the bloodstream once Chronocort® is taken and what affects it has on other hormones in the body. Since Chronocort® is anticipated to mimic the same release pattern of cortisol in the body, it is hoped that patients with CAH will be treated more effectively to manage their disease.

Study Overview

• Status: Completed
• Conditions: Congenital Adrenal Hyperplasia; Adrenal Insufficiency; Endocrine Disease
• Intervention / Treatment: Drug: Hydrocortisone Modified Release Capsules

Detailed Description

This study is a Phase 2 pilot study to characterize and examine the pharmacokinetics and efficacy profile of Chronocort® in adults with congenital adrenal hyperplasia (CAH). It is designed as a two-part, single cohort, open label, multiple dose Phase 2 pilot study to: (Part A) characterize and examine the pharmacokinetics (PK) and disease bio-marker behavior following short-term dosing with Chronocort®; and to (Part B) examine the disease control after six months dose titration with Chronocort® in adults with CAH.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892-1932
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Known CAH due to 21-hydroxylase deficiency (classic CAH) based on hormonal and genetic testing currently treated with hydrocortisone, prednisone, prednisolone or dexamethasone on a stable dosage for a minimum of 3 months.
2. Male or female patients aged 18 and above.
3. Provision of signed written informed consent.
4. Good general health.
5. Females of childbearing potential must have a negative pregnancy test initially and at all visits. Females who are engaging in sexual intercourse must be using a medically acceptable method of contraception (as defined in the protocol, section 10.5).
6. Plasma renin activity must be within the clinically acceptable range at screening (less than 1.5 times upper normal range).

Exclusion Criteria:

1. Co-morbid condition requiring daily administration of a medication that induces hepatic enzymes or interferes with the metabolism of glucocorticoids.
2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine above the normal range or elevated liver function tests (ALT or AST) > 2 times the upper limits of normal.
3. Females who are pregnant or lactating.
4. Women taking an estrogen-containing oral contraceptive pill and who have taken it within 6 weeks of recruitment.
5. Patients taking spironolactone.
6. Patients on inhaled or oral steroids apart from treatment for CAH.
7. Patients with any other significant medical or psychiatric conditions that in the opinion of the Investigator would preclude participation in the trial.
8. Participation in another clinical trial of an investigational or licensed drug or device within the 3 months prior to inclusion in this study.
9. Patients with history of bilateral adrenalectomy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydrocortisone Modified Release Capsules; Chronocort Modified Release Capsules, 5mg, 10mg and 20mg Dosing frequency twice-daily (mane and nocte) Dose setting by titration to achieve optimal biochemical and therapeutic response	Drug: Hydrocortisone Modified Release Capsules; Patients with congenital adrenal hyperplasia standardised on conventional therapy is enrolled onto the study and treatment is switched to Chronocort, initially for pharmacokinetic assessment followed by longer-term biochemical and efficacy assessment; Other Names: Chronocort

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Profile (Cmax) Following Short-term Treatment With Chronocort® in Adult Patients With Congenital Adrenal Hyperplasia	The maximum plasma concentration (Cmax) of chronocort	24 hours
Pharmacokinetic Profile (AUC0-24) Following Short-term Treatment With Chronocort® in Adult Patients With Congenital Adrenal Hyperplasia	Area under the curve (AUC) from 0 to 24 hours (sampling occurs at the following timepoints: 2300, 0100, 0300, 0500, 0600, 0700, 0800, 0900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1900, 2100, 2300hrs)	24 hours (at 2300, 0100, 0300, 0500, 0600, 0700, 0800, 0900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1900, 2100, 2300hrs)
Pharmacokinetic Profile (Tmax) Following Short-term Treatment With Chronocort® in Adult Patients With Congenital Adrenal Hyperplasia	Time to maximum plasma concentration (tmax)	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Patients With 17-OHP and Androstenedione Levels at 0700h Within Proposed Optimal Ranges Whilst on Chronocort and Whilst on Standard Therapy (at Baseline)	Proposed optimal ranges of 17-OHP: 300-1200ng/dl Proposed optimal ranges of androstenedione: 40-150ng.dl for males and 30-200ng/dl for females	Specific time point (0700hrs)
17-OHP Levels at 0700h, 1700h and 2300h	17-OHP levels at 0700h, 1700h and 2300h	Specified time points (0700h, 1700h and 2300h)
Androstenedione Levels at 0700h, 1700h and 2300h	Androstenedione levels at 0700h, 1700h and 2300h	Specified time points (0700h, 1700h and 2300h)
ACTH Levels at 0700h, 1700h and 2300h	ACTH levels at 0700h, 1700h and 2300h	Specified time points (0700h, 1700h and 2300h)
AUC Values (Nmol*h/L) for Androstenedione	AUC values (nmol*h/L) for Androstenedione for the following reporting periods: 24 hours (2300-2300h), 2300-0700h, 0700-1500h and 1500-2300h	Specific time points (2300-2300h, 2300-0700h, 0700-1500h and 1500-2300h)
AUC Values (Nmol*h/L) for 17-OHP	AUC values (nmol*h/L) for 17-OHP for the following reporting periods: 24 hours (2300-2300h), 2300-0700h, 0700-1500h and 1500-2300h	Specific time points (2300-2300h, 2300-0700h, 0700-1500h and 1500-2300h)
AUC Values (Pmol*h/L) for ACTH	AUC values (pmol*h/L) for ACTH for the following reporting periods: 24 hours (2300-2300h), 2300-0700h, 0700-1500h and 1500-2300h	Specific time points (2300-2300h, 2300-0700h, 0700-1500h and 1500-2300h)

Collaborators and Investigators

• Sponsor: Diurnal Limited
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Deborah P Merke, BS, MS, MD, National Institutes of Health Clinical Center (CC)

Publications and helpful links

General Publications

• Mallappa A, Sinaii N, Kumar P, Whitaker MJ, Daley LA, Digweed D, Eckland DJ, Van Ryzin C, Nieman LK, Arlt W, Ross RJ, Merke DP. A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2015 Mar;100(3):1137-45. doi: 10.1210/jc.2014-3809. Epub 2014 Dec 11.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: November 20, 2012
• First Submitted That Met QC Criteria: November 25, 2012
• First Posted (Estimate): November 28, 2012

Study Record Updates

• Last Update Posted (Actual): May 17, 2017
• Last Update Submitted That Met QC Criteria: April 11, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: cortisol; adrenal; glucocorticoids; congenital adrenal hyperplasia
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Gonadal Disorders; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Adrenal Gland Diseases; Steroid Metabolism, Inborn Errors; Hyperplasia; Endocrine System Diseases; Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Adrenocortical Hyperfunction; Adrenal Insufficiency; Anti-Inflammatory Agents; Hydrocortisone
• Other Study ID Numbers: DIUR-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No