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

Study Overview
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Brief Summary
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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.

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 Any subjects not meeting the inclusion/exclusion criteria following these blood tests will be withdrawn from this study.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

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

Conditions
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Congenital Adrenal Hyperplasia

Intervention / Treatment
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* Drug: Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with CAH who have successfully completed a clinical trial with the current formulation of Chronocort®. Provision of signed written informed consent. Exclusion Criteria: Co-morbid condition requiring daily administration of a medication (or use of any medications/supplements) 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 ULN]). Females who are pregnant or lactating. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH. 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. 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®. Subjects unable to comply with the requirements of the protocol. Subjects who routinely work night shifts and so do not sleep during the usual nighttime hours.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chronocort®<br>Chronocort® modified release hydrocortisone | Drug: Hydrocortisone<br>* Modified release hydrocortisone<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term efficacy of Chronocort, as assessed by total daily dose of Chronocort in mg/day of hydrocortisone and by Body Surface Area (BSA). | Long-term efficacy of Chronocort, as assessed by total daily dose of Chronocort in mg/day of hydrocortisone during the study, and by BSA. | 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. | 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. | 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 | 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. | 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 Standarad Deviation Score (SDS) of 17-OHP. | 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. | 5.5 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. | 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. | 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. | 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). | 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. | 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). | 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 at each visit in bone turnover markers | Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in bone turnover markers (CTX and osteocalcin). | 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 | Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in total Testosterone | 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. | Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline in fasting insulin, blood glucose levels, and HbA1c at each visit. | 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 hsCRP and PRA | Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline in hsCRP and PRA at each visit | 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 body composition. | 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). | 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 at each visit in Quality of Life | Change from pre-Chronocort® baseline at each visit in Quality of Life, as assessed by SF-36, MAF and EQ-5D. | 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 incidence of dose titrations. | Long-term efficacy of Chronocort, as assessed by change from pre-Chronocort® baseline at each visit in incidence of dose titrations. | 5.5 years (Assessed at visits: Visit 2, Visit 3, Visit 4 then every 6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extension study