A Study of the Efficacy, Safety and Tolerability of Chronocort in Treating CAH

A Phase III Extension Study of Efficacy, Safety and Tolerability of Chronocort® in the Treatment of Congenital Adrenal Hyperplasia

Subjects completing study DIUR-005 and those who have already completed study DIUR-003 will be offered the opportunity either to continue Chronocort® therapy or to switch from their current glucocorticoid therapy to Chronocort® in this open-label study.

Study Overview

• Status: Completed
• Conditions: Congenital Adrenal Hyperplasia
• Intervention / Treatment: Drug: Hydrocortisone

Detailed Description

All subjects will have a screening visit prior to the baseline assessment to allow DIUR-006 procedures to be fully explained and informed consent to be given by the subject. For subjects from DIUR-003 this screening visit will include safety blood tests. Any subjects not meeting the inclusion/exclusion criteria following these blood tests will be not be entered into the study.

All subjects will then return for the baseline visit. For subjects entering from study DIUR-003 the full set of baseline assessments will be completed, including 2 blood samples (one at 09:00 and one at 13:00 hours) for 17-OHP and A4. For subjects entering from DIUR-005, test results from their last visit in the feeder study (Visit 4) will be used for this baseline assessment, with the 09:00 and 13:00 hour results taken from the 24-hour hormone profiles conducted at the visit. Any subjects not meeting the inclusion/exclusion criteria following these blood tests will be withdrawn from this study.

Once the baseline assessments are completed, the subjects will be given sufficient Chronocort® to use until the next visit at Week 4. Subjects from study DIUR-005 who were previously on Chronocort® will continue on the same dose of Chronocort® that they were receiving at the end of the feeder study. Subjects from study DIUR-005 on standard therapy and subjects from study DIUR-003 will have their initial dose of Chronocort® determined using the hydrocortisone equivalent of baseline therapy.

All subjects will return to the study centre at 4, 12 and 24 weeks after starting study DIUR-006 for additional blood tests and dose titration, if necessary. Visits thereafter will take place at 6-monthly intervals. If there is a change of dose, an interim visit or phone call will be needed inbetween the 6-monthly visits.

All subjects will receive telephone calls at 3 monthly intervals, and unscheduled visits will be arranged if necessary. Subjects will also be provided with Chronocort® supplies from the study pharmacy at 3-monthly or 6-monthly intervals.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 3

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

Description

Inclusion Criteria:

1. Subjects with CAH who have successfully completed a clinical trial with the current formulation of Chronocort®.
2. Provision of signed written informed consent.

Exclusion Criteria:

1. Co-morbid condition requiring daily administration of a medication (or use of any medications/supplements) that interferes with the metabolism of glucocorticoids.
2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the ULN or elevated liver function tests (ALT or AST >2 times ULN]).
3. Females who are pregnant or lactating.
4. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH.
5. History of malignancy (other than basal cell carcinoma successfully treated >6 months prior to entry into the study).
6. Subjects with a history of bilateral adrenalectomy.
7. Participation in another clinical trial of an investigational or licensed drug or device within the 3 months prior to inclusion in this study, except for another clinical trial with the current formulation of Chronocort®.
8. Subjects unable to comply with the requirements of the protocol.
9. Subjects who routinely work night shifts and so do not sleep during the usual nighttime hours.

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: Chronocort®; Chronocort® modified release hydrocortisone	Drug: Hydrocortisone; Modified release hydrocortisone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability - Number of Participants With Adrenal Insufficiency	Safety and tolerability of Chronocort® over time, as assessed by signs and symptoms of adrenal insufficiency or over-treatment throughout the study. Signs and symptoms of adrenal insufficiency included sudden weight loss, sudden weight gain, lack of appetite, increased appetite, nausea, vomiting, headache, blurred vision, fatigue, weakness, dizziness, light-headedness, syncope, sleeping difficulties and increased acne. Number of participants who experienced adrenal insufficiency due to glucocorticoid (GC) over replacement and under replacement are reported.	Up to approximately 5 years and 11 months
Safety and Tolerability - Number of Participants Who Used Sick Day Medication	Safety and tolerability of Chronocort, as assessed by number of participants who used sick day medication throughout the study. Data are presented for number of participants taking medication from sick day packs and number of participants taking medication that was not from sick day packs.	Up to approximately 5 years and 11 months
Safety and Tolerability - Number of Participants Who Experienced at Least One Adrenal Crisis	Safety and tolerability of Chronocort, as assessed by the number of participants who experienced adrenal crises throughout the study. Adrenal crisis was defined as follows: a) Major impairment of general health with at least two of the following signs/symptoms: Hypotension (systolic blood pressure <100 mmHg); Nausea or vomiting; Severe fatigue; Fever; Somnolence; Hyponatraemia (<132 mmol/L) or hyperkalaemia (as judged by characteristic electrocardiogram [ECG] changes); Hypoglycaemia and b) Parenteral glucocorticoid (hydrocortisone) administration followed by clinical improvement: Grade 1: outpatient care only; Grade 2: hospital care (general ward); Grade 3: admission to intensive care unit; Grade 4: death from adrenal crisis (with or without parenteral glucocorticoid administration).	Up to approximately 5 years and 11 months
Safety and Tolerability - Number of Participants With Adverse Events (AEs)	Safety and tolerability of Chronocort, as assessed by the number of participants with at least 1 AE per specified AE category throughout the study. An AE was any untoward medical occurrence in a participant administered the study drug that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, was a congenital anomaly or birth defect, was infection that required treatment parenteral antibiotics, other important medical events which based on medical or scientific judgement might jeopardize the participants, or might require medical or surgical intervention to prevent any of the above. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.	Up to approximately 5 years and 11 months
Safety Laboratory Assessments - Number of Participants With a Shift in Laboratory Parameters Baseline Values to the Maximum Values	Safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline in safety laboratory assessments throughout the study. Participants with a parameter value that shifted from baseline (within reference range) to a value above the reference range for a maximum value on-treatment.	Baseline up to approximately 5 years and 11 months
Safety Laboratory Assessments - Number of Participants With a Shift in Laboratory Parameters Baseline Values to the Minimum Values	Safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline in safety laboratory assessments throughout the study. Participants with a parameter value that shifted from baseline (within reference range) to a value below the reference range for a minimum value on-treatment.	Baseline up to approximately 5 years and 11 months
Safety and Tolerability - Change From Pre-Chronocort Baseline to Month 30 in Vital Signs - Diastolic Blood Pressure	Long-term safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline to Month 30 in vital signs - Diastolic blood pressure.	Baseline, Month 30
Safety and Tolerability - Change From Pre-Chronocort Baseline to Month 30 in Vital Signs - Systolic Blood Pressure	Long-term safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline to Month 30 in vital signs - Systolic blood pressure.	Baseline, Month 30
Safety and Tolerability - Change From Pre-Chronocort Baseline to Month 30 in Vital Signs - Pulse Rate	Long-term safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline to Month 30 in vital signs - Pulse rate.	Baseline, Month 30
Safety and Tolerability - Change From Pre-Chronocort Baseline to Month 30 in Vital Signs - Respiratory Rate	Long-term safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline to Month 30 in vital signs - Respiratory rate.	Baseline, Month 30
Safety and Tolerability - Change From Pre-Chronocort Baseline to Month 30 in Vital Signs - Body Temperature	Long-term safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline to Month 30 in vital signs - body temperature.	Baseline, Month 30
Safety and Tolerability - Change From Pre-Chronocort Baseline to Month 30 in Vital Signs - Body Weight	Long-term safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline to Month 30 in vital signs - Body Weight.	Baseline, Month 30
Safety and Tolerability - Change From Pre-Chronocort Baseline to Month 30 in Vital Signs - BMI	Long-term safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline to Month 30 in vital signs - BMI.	Baseline, Month 30
Safety and Tolerability - Change From Pre-Chronocort Baseline to Month 30 in Vital Signs - Waist Circumference	Long-term safety and tolerability of Chronocort, as assessed by change from pre-Chronocort baseline to Month 30 in vital signs - Waist circumference.	Baseline, Month 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Daily Dose of Chronocort in Milligrams (mg)/Day of Hydrocortisone During the Time Interval Baseline to Week 4 and Month 18 to Month 24	Total daily dose was summarized in mg/day of hydrocortisone where 1 mg of Chronocort equals 1 mg of hydrocortisone. Baseline was defined as the first visit of Study DIUR-006 for all participants.	Baseline to Week 4 and Month 18-24
Total Daily Dose of Chronocort in mg/Day/m^2 of Hydrocortisone by BSA During the Time Interval Baseline to Week 4 and Month 18 to Month 24	Total daily dose of Chronocort per BSA was summarized in mg/day/m^2 of hydrocortisone where 1 mg of Chronocort equals 1 mg of hydrocortisone. The BSA (m^2) was calculated from baseline values using the Dubois formula [weight (kg)^0.425] x [Height (cm)^0.725)] x 0.007184. Baseline was defined as the first visit of Study DIUR-006 for all participants.	Baseline to Week 4 and Month 18-24
Number of Participants Achieving Disease Control at 09:00 Hours and 13:00 Hours for 17-hydroxyprogesterone (17-OHP)	Long-term efficacy of Chronocort, as assessed by participants achieving disease control at 09:00 hours and 13:00 hours for 17-OHP. Data are presented for the number of participants considered responders and non-responders. A participant was considered a responder if their results were in the optimal range (defined as 1.2 to 36.4 nanomoles [nmol]/liter [L]) for 17-OHP.	Baseline and Week 24
Number of Participants Achieving Disease Control at 09:00 Hours and 13.00 Hours for Androstenedione (A4)	Long-term efficacy of Chronocort, as assessed by participants achieving disease control at 09:00 hours and 13:00 hours for A4. Data are presented for the number of participants considered responders and non-responders. A participant was considered a responder if their results were in the reference range (defined as 1.4 to 5.2 nmol/L in males and 1.0 to 7.0 nmol/L in females) for A4.	Baseline and Week 24
Change From Pre-Chronocort Baseline at Month 24 in Bone Turnover Markers - Osteocalcin	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in bone turnover markers (osteocalcin).	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Bone Turnover Markers - C-Terminal Cross-linked Telopeptide (CTX)	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in bone turnover markers - CTX.	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Total Testosterone	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in total testosterone.	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Fasting Insulin	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in fasting insulin.	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Fasting Glucose	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in fasting glucose.	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Glycated Hemoglobin (HbA1c)	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in HbA1c.	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in High Sensitivity C-reactive Protein (hsCRP)	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in hsCRP.	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Plasma Renin Activity (PRA)	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in PRA.	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Body Composition - Total Lean Mass	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in body composition (Dual energy X-ray absorptiometry [DEXA]) - total lean mass	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Body Composition - Bone Mineral Density	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in body composition (DEXA) - bone mineral density.	Baseline, Month 24
Change From Pre-Chronocort Baseline at Month 24 in Body Composition - Total Fat Mass	Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline at Month 24 in body composition (DEXA) - total fat mass	Baseline, Month 24
Change From Pre-Chronocort Baseline in Quality of Life - Medical Outcome Short Form Health Survey Form 36 (SF-36) Score at Months 12 and 18	The SF-36 questionnaire has 36 questions composing the scale that represent 8 domains: 1) physical functioning, role physical, 2) bodily pain, 3) general health, 4) vitality, 5) social functioning, 6) role, 7) emotional, and 8) mental health. The scores for the 8 domains were combined into two summary scores: the physical component summary (PCS) score and the mental component summary (MCS) score. Scores of the first four health items (1 - 4) were aggregated to derive the PCS ranging from 0 (worst) to 100 (best), where higher scores indicated good health condition. Scores of last four items (5 - 8) were aggregated to derive the MCS ranging from 0 (worst) to 100 (best), where higher scores indicated good health condition.	Baseline, Months 12 and 18
Change From Pre-Chronocort Baseline in Quality of Life - Multidimensional Assessment of Fatigue (MAF) Global Fatigue Index (GFI) Score at Months 12 and 18	MAF is a 16-item scale that measures fatigue according to 4 dimensions; degree and severity, distress that it causes, timing of fatigue, and its impact of various activities of daily living. The GFI score was calculated using a standard method specific to the MAF questionnaire. This combines the responses to the questionnaire to give one score ranging from 1 (no fatigue) to 50 (severe fatigue), with a higher score indicating more severe fatigue, fatigue distress, or impact on activities of daily living. Decreases from baseline indicate improvement.	Baseline, Months 12 and 18
Change From Pre-Chronocort Baseline in Quality of Life - Standardized Health Questionnaire 5-Dimension (EQ-5D) Index Score and Visual Analogue Scale (VAS) Score at Months 12 and 18	The EQ-5D questionnaire consists of 2 parts, the EQ-5D descriptive system and the EQ VAS. The descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression each with 5 problem levels (1-none to 5-extreme). The results from the dimensions were combined using a standard method specially designed for the EQ-5D questionnaire to give a single index value (EuroQol Research Foundation) with scores ranging from 0 (no problems) to 1 (extreme problems). The EQ VAS is a visual scale in which the participant gives a single score between 0 (worst health state) and 100 (best health state).	Baseline, Months 12 and 18
Number of Participants With Dose Titrations	Long-term efficacy of Chronocort, as assessed by number of participants with dose titrations. Data are presented for number of participants with a dose increase, dose decrease, both a dose increase, and a dose decrease or no dose titration at specified timepoints.	Baseline to Week 4 and Month 18

Collaborators and Investigators

• Sponsor: Diurnal Limited
• Investigators: Principal Investigator: Principal Investigator, Diurnal Limited

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2016
• Primary Completion (Actual): July 13, 2022
• Study Completion (Actual): July 13, 2022

Study Registration Dates

• First Submitted: August 22, 2016
• First Submitted That Met QC Criteria: February 20, 2017
• First Posted (Actual): February 23, 2017

Study Record Updates

• Last Update Posted (Actual): October 28, 2024
• Last Update Submitted That Met QC Criteria: October 24, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Extension study
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Gonadal Disorders; Congenital Abnormalities; Adrenal Gland Diseases; Disorders of Sex Development; Urogenital Abnormalities; Steroid Metabolism, Inborn Errors; Hyperplasia; Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Anti-Inflammatory Agents; Hydrocortisone
• Other Study ID Numbers: DIUR-006

Plan for Individual participant data (IPD)

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