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

• ClinicalTrials.gov Identifier: NCT03062280
• Recruitment Status: Completed
• First Posted: February 23, 2017
• Last Update Posted: October 18, 2022
• Sponsor: Diurnal Limited
• Information provided by (Responsible Party): Diurnal Limited

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Congenital Adrenal Hyperplasia	Drug: Hydrocortisone	Phase 3

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 Any subjects not meeting the inclusion/exclusion criteria following these blood tests will be withdrawn from this study.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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 92 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Extension Study of Efficacy, Safety and Tolerability of Chronocort® in the Treatment of Congenital Adrenal Hyperplasia
• Actual Study Start Date: August 18, 2016
• Actual Primary Completion Date: July 13, 2022
• Actual Study Completion Date: July 13, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Chronocort®; Chronocort® modified release hydrocortisone	Drug: Hydrocortisone; Modified release hydrocortisone

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability of Chronocort over time, as assessed by signs and symptoms of adrenal insufficiency. [ Time Frame: 5.5 years (Assessed at visits: Visit 2, Visit 3, Visit 4 then every 6 months and final visit) ]
   Safety and tolerability of Chronocort® over time, as assessed by signs and symptoms of adrenal insufficiency or over-treatment throughout the study.
2. Safety and tolerability of Chronocort, as assessed by incidence of use of sick day rules. [ Time Frame: 5.5 years (Assessed at visits: Visit 2, Visit 3, Visit 4 then every 6 months and final visit) ]
   Safety and tolerability of Chronocort, as assessed by incidence of use of sick day rules throughout the study.
3. Safety and tolerability of Chronocort, as assessed by the occurrence of adrenal crises. [ Time Frame: 5.5 years (Assessed at visits: Visit 2, Visit 3, Visit 4 then every 6 months and final visit) ]
   Safety and tolerability of Chronocort, as assessed by the occurrence of adrenal crises throughout the study.
4. Safety and tolerability of Chronocort, as assessed by the occurrence of adverse events (AEs). [ Time Frame: 5.5 years ]
   Safety and tolerability of Chronocort, as assessed by the occurrence of AEs throughout the study.
5. Safety and tolerability of Chronocort, as assessed by change from pre-Chronocort® baseline in safety laboratory assessments. [ Time Frame: 5.5 years (Assessed at visits: Screening [V0], Baseline [V1], Visit 4 then every 6 months and Final visit) ]
   Safety and tolerability of Chronocort, as assessed by change from pre-Chronocort® baseline in safety laboratory assessments throughout the study.
6. Safety and tolerability of Chronocort, as assessed by change from pre-Chronocort® baseline in vital signs, weight, body mass index (BMI) and waist circumference. [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 4 then every 6 months and Final visit) ]
   Safety and tolerability of Chronocort, as assessed by change from pre-Chronocort® baseline in vital signs, weight, body mass index (BMI) and waist circumference throughout the study.

Secondary Outcome Measures :

1. Long-term efficacy of Chronocort, as assessed by total daily dose of Chronocort in mg/day of hydrocortisone and by Body Surface Area (BSA). [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 2, Visit 3, Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by total daily dose of Chronocort in mg/day of hydrocortisone during the study, and by BSA.
2. Long-term efficacy of Chronocort, as assessed by serum 17-OHP levels. [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 2, Visit 3, Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by serum 17-OHP levels, when measured at two time points (at 09:00 and 13:00 hours at each study visit) to assess disease control in the optimal range at both time points, and by the proportion of dose given at night.
3. Long-term efficacy of Chronocort, as assessed by serum A4 levels [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 2, Visit 3, Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by serum A4 levels, when measured at two time points (at 09:00 and 13:00 hours at each study visit) to assess disease control in the normal range at both time points, and by the proportion of dose given at night.
4. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline in Standarad Deviation Score (SDS) of 17-OHP. [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 2, Visit 3, Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline in SDS of 17-OHP, when measured at two time points (at 09:00 and 13:00 hours at each study visit) and the mean of the two timepoints.
5. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline in SDS of A4. [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 2, Visit 3, Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline in SDS of A4, when measured at two time points (at 09:00 and 13:00 hours at each study visit) and the mean of the two timepoints.
6. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline in absolute values of 17-OHP. [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 2, Visit 3, Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline in absolute values of 17-OHP, when measured at two time points (09:00 and 13:00 hours at each study visit).
7. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline in absolute values of A4. [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 2, Visit 3, Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort baseline in absolute values of A4, when measured at two time points (09:00 and 13:00 hours at each study visit).
8. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in bone turnover markers [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in bone turnover markers (CTX and osteocalcin).
9. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in total Testosterone [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 4 then every 6 months and Final visit) ]
   Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in total Testosterone
10. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline in fasting insulin, blood glucose levels, and HbA1c. [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 4 then every 6 months and Final visit) ]
    Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline in fasting insulin, blood glucose levels, and HbA1c at each visit.
11. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in hsCRP and PRA [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 4 then every 6 months and Final visit) ]
    Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline in hsCRP and PRA at each visit
12. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in body composition. [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 4 then every 6 months) ]
    Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline in body composition (DEXA)(fat mass, lean mass and total bone density) (except in Germany).
13. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in Quality of Life [ Time Frame: 5.5 years (Assessed at visits: Baseline [V1], Visit 4 then every 6 months and Final visit) ]
    Change from pre-Chronocort® baseline at each visit in Quality of Life, as assessed by SF-36, MAF and EQ-5D.
14. Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in incidence of dose titrations. [ Time Frame: 5.5 years (Assessed at visits: Visit 2, Visit 3, Visit 4 then every 6 months) ]
    Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in incidence of dose titrations.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Maryland

National Institutes of Health Clinical Center

Bethesda, Maryland, United States, 20892-1932

Sponsors and Collaborators

Diurnal Limited

Investigators

• Principal Investigator: Debbie Merke, MD; National Institutes of Health (NIH)

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Diurnal Limited
• ClinicalTrials.gov Identifier: NCT03062280
• Other Study ID Numbers: DIUR-006
• First Posted: February 23, 2017
• Last Update Posted: October 18, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Diurnal Limited:

Extension study

Additional relevant MeSH terms:

Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Hyperplasia; Pathologic Processes; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Steroid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Adrenal Gland Diseases; Endocrine System Diseases; Gonadal Disorders; Hydrocortisone; Anti-Inflammatory Agents