Comparison of Chronocort Versus Standard Hydrocortisone Replacement Therapy in Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia

Study Overview
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Brief Summary
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This study is a randomized, double-blind, active-controlled, phase III study of Chronocort® compared with immediate-release hydrocortisone replacement therapy in participants aged 16 years and over with Congenital Adrenal Hyperplasia.

Detailed Description
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The study will compare the efficacy, safety and tolerability of twice daily Chronocort with twice daily immediate release hydrocortisone replacement therapy (IRHC) (Cortef®) over a randomized treatment period of up to 52 weeks in participants aged 16 years and over with known classic Congenital Adrenal Hyperplasia (CAH) due to 21 hydroxylase deficiency. The primary efficacy assessment of biochemical responder rate and the key secondary assessment of dose responder rate will be assessed after 52 weeks of randomized treatment.

Official Title
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A Randomized, Double-Blind, Active-Controlled, Phase 3 Study of Chronocort Compared With Immediate-Release Hydrocortisone Replacement Therapy in Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia

Conditions
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Congenital Adrenal Hyperplasia

Intervention / Treatment
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* Drug: Chronocort
* Drug: Cortef


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants must be aged 16 years or older at the time of signing the informed consent/assent. In participants aged <18 years, height velocity must be less than 2 cm/year in the last year and puberty must be completed (Tanner stage V). Participants with known classic CAH due to 21 hydroxylase deficiency diagnosed in childhood with documented (at any time) elevated 17-OHP and with or without elevated A4 and currently treated with hydrocortisone, prednisone, prednisolone or dexamethasone (or a combination of the aforementioned glucocorticoids) and on stable glucocorticoid therapy for a minimum of 3 months. Participants who are receiving fludrocortisone must be on a documented stable dose for a minimum of 3 months prior to enrollment and must have stable renin levels at screening. Female participants of childbearing potential and all male participants must agree to the use of an accepted method of contraception during the study. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and she is either not a woman of childbearing potential (WOCBP) or has a negative pregnancy test at entry into the study. Note: females presenting with oligomenorrhea or amenorrhea who are aged ≤55 years should be considered potentially fertile and therefore should undergo pregnancy testing like all other female participants. Capable of giving signed informed consent/assent which includes compliance with requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: Clinical or biochemical evidence of hepatic or renal disease e.g. creatinine >2 times the upper limit of normal (ULN) or elevated liver function tests (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >2 times the ULN). History of bilateral adrenalectomy. History of malignancy (other than basal cell carcinoma successfully treated >26 weeks prior to entry into the study). Participants who have type 1 diabetes or receive regular insulin, have uncontrolled diabetes, or have a screening HbA1c greater than 8%.. Persistent signs of adrenal insufficiency or the participant does not tolerate treatment at the end of the 4-week run-in period. Participants with any other significant medical or psychiatric conditions that in the opinion of the Investigator would preclude participation in the study. Participants on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH. Co-morbid condition requiring daily administration of a medication or consumption of any material that interferes with the metabolism of glucocorticoids. Participants who are receiving <10 mg hydrocortisone dose at screening or the hydrocortisone dose equivalent. Participants anticipating regular prophylactic use of additional steroids e.g. for strenuous exercise. Participation in another clinical study of an investigational or licensed drug or device within the 12 weeks prior to screening. Inclusion in any natural history or translational research study that would require evaluation of androgen levels during the study period outside of this protocol's assessments. Participants who have previously been exposed to Chronocort in any Diurnal study. Participants who routinely work night shifts and so do not sleep during the usual night-time hours. Participants, who in the opinion of the Investigator, will be unable to comply with the requirements of the protocol. Participants with a known hypersensitivity to any of the components of the Chronocort capsules, the Cortef tablets, or the placebo capsules. Participants with congenital galactosemia, malabsorption of glucose and galactose, or who are lactase deficient. Participants with a body weight of 45 kg or less.

Ages Eligible for Study
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Minimum Age: 16 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chronocort<br>Hydrocortisone modified-release capsule - Chronocort®. 63 subjects will be randomised to this group using an interactive response technology (IRT). | Drug: Chronocort<br>* Over-encapsulated hydrocortisone modified-release capsules for oral administration - 5mg and 10mg<br>* Other names: Hydrocortisone modified-release capsules;|
| Active Comparator: Cortef<br>Immediate-release hydrocortisone capsule (IRHC) - Cortef. 63 subjects will be randomised to this group using an interactive response technology (IRT). | Drug: Cortef<br>* Over-encapsulated immediate-release hydrocortisone capsules for oral administration - 5mg and 20mg<br>* Other names: Immediate-release hydrocortisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare Chronocort to IRHC in terms of biochemical responder rate after 52 weeks of randomized treatment - 17-OHP concentration | Biochemical control defined as a 17-OHP concentration equal to or below the upper limit for optimal control. | 52 weeks | 
| To compare Chronocort to IRHC in terms of biochemical responder rate after 52 weeks of randomized treatment - A4 concentration | Biochemical control defined as a A4 concentration equal to or below the upper limit for optimal control. | 52 weeks | 
| To compare Chronocort to IRHC in terms of biochemical responder rate after 52 weeks of randomized treatment - Total daily dose of Hydrocortisone | Biochemical control defined as receiving after 52 weeks of randomized treatment a total daily dose of hydrocortisone of not more than 25 mg (if the participant was in biochemical control at baseline) or not more than 30 mg (if the participant was not in biochemical control at baseline). | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare Chronocort to IRHC in terms of dose responder rate after 52 weeks of randomized treatment - Total daily dose | A dose responder defined as a participant receiving after 52 weeks of randomized treatment a total daily dose of hydrocortisone of not more than 25 mg. | 52 weeks | 
| To compare Chronocort to IRHC in terms of dose responder rate after 52 weeks of randomized treatment - 17-OHP concentration | A dose responder defined as a participant in biochemical control at the 08:00 hours assessment after 52 weeks of randomized treatment (where in biochemical control is defined as a 17-OHP concentration equal to or below the upper limit for optimal control. | 52 weeks | 
| To compare Chronocort to IRHC in terms of dose responder rate after 52 weeks of randomized treatment - A4 concentration | A dose responder defined as a participant in biochemical control at the 08:00 hours assessment after 52 weeks of randomized treatment (where in biochemical control is defined as an A4 concentration equal to or below the upper limit for optimal control. | 52 weeks | 
| To compare Chronocort to IRHC in terms of total daily dose after 52 weeks of randomized treatment. | The total daily dose (mg) after 52 weeks of randomized treatment. The difference (Chronocort minus IRHC) between the mean total daily dose after 52 weeks of randomized treatment in each treatment arm will be estimated in the Fatigue Assessment Scale (FAS). Superiority of Chronocort to IRHC with respect to total daily dose after 52 weeks of randomized treatment will be declared if the 95% CI for the difference in means lies wholly below zero, provided that dose superiority of Chronocort to IRHC has been declared under the first key secondary efficacy objective. | 52 weeks | 
| To compare Chronocort to IRHC in terms of biochemical responders at 4, 10, 16, and 34 weeks after randomization. | Whether or not the participant is a biochemical responder at 08:00 hours at 4, 10, 16 and 34 weeks after randomization are compared between treatment arms by calculating the difference in proportion of participants responding. These outcome variables are to be analyzed in the same manner as the primary efficacy outcome variable. | 4, 10, 16 and 34 weeks after randomization | 
| To compare Chronocort to IRHC in terms of dose responders at 10, 16, and 34 weeks after randomization. | Whether or not the participant is a dose responder at 08:00 hours at 10, 16 and 34 weeks after randomization are compared between treatment arms by calculating the difference in proportion of participants responding. These outcome variables are to be analyzed in the same manner as the first key secondary outcome variable. | 10, 16 and 34 weeks after randomization | 
| To compare Chronocort to IRHC in terms of total daily dose at 10, 16, and 34 weeks after randomization. | Total daily dose at 10, 16 and 34 weeks after randomization are compared between treatment arms by calculating the difference in mean total daily dose. These outcome variables are to be analyzed in the same manner as the second key secondary outcome variable. | 10, 16 and 34 weeks after randomization | 
| To compare Chronocort to IRHC in terms of biochemical control at 10, 16, and 34 weeks after randomization. | Whether or not the participant is in biochemical control (provided total daily dose is not more than 30 mg) at 08:00 hours at 4, 10, 16, 34 and 52 weeks after randomization are compared between treatment arms by calculating the difference in proportion of participants in control. | 4, 10, 16, 34, and 52 weeks after randomization | 
| To compare Chronocort to IRHC in terms of the impact on 17 OHP range. | The difference between the 08:00 and 13:00 measurements of 17-OHP levels at 4, 10, 16, 34, and 52 weeks after randomization and their changes from baseline will be summarized and compared between treatment arms. | 4, 10, 16, 34, and 52 weeks after randomization | 
| To compare Chronocort to IRHC in terms of the impact on A4 range | The difference between the 08:00 and 13:00 measurements of A4 levels at 4, 10, 16, 34, and 52 weeks after randomization and their changes from baseline will be summarized and compared between treatment arms. | 4, 10, 16, 34, and 52 weeks after randomization | 
| To compare Chronocort to IRHC in terms of the impact on mean 17-OHP and A4 | The mean of the 08:00 and 13:00 measurements of 17-OHP levels and A4 levels at 4, 10, 16, 34, and 52 weeks after randomization and their changes from baseline will be summarized and compared between treatment arms. | 4, 10, 16, 34, and 52 weeks after randomization | 
| To compare Chronocort to IRHC in terms of the impact on glucocorticoid dose - Total daily dose | The total daily glucocorticoid dose at 4, 10, 16, 34, and 52 weeks after randomization will be summarized and compared between treatment arms. | 4, 10, 16, 34, and 52 weeks after randomization | 
| To compare Chronocort to IRHC in terms of the impact on glucocorticoid dose - Biochemical control | The relationship between daily glucocorticoid dose and biochemical control at 52 weeks after randomization will be explored. | 52 weeks | 
| To compare Chronocort to IRHC in terms of changes in menstrual regularity. | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in menstrual regularity (only in pre menopausal women without hysterectomy and not using hormonal contraception) will be summarized and compared between treatment arms. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on luteinizing hormone (LH) levels. | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in LH levels (men only) will be summarized and compared between treatment arms. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on testicular adrenal rest tumors (TART) size. | The change from baseline to 34 and 52 weeks of randomized treatment in size of TART (men only) will be summarized and compared between treatment arms. | Baseline to 34 and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on sperm count. | The change from baseline to 34 and 52 weeks of randomized treatment in sperm count (men only) will be summarized and compared between treatment arms. | Baseline to 34 and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on subjective hirsutism in female participants | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in subjective hirsutism using a Visual Analog Scale (VAS) (women only), which is a 10cm scale ranging from 'No Hair' to 'Most Hair Growth Ever Experienced' will be summarized and compared between treatment arms. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on objective hirsutism in female participants | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in objective hirsutism using the Ferriman-Gallwey score (women only) will be summarized and compared between treatment arms. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on subjective acne in female participants. | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in subjective acne using a VAS (women only) will be summarized and compared between treatment arms. The scale used is a 10cm scale ranging from 'No Acne' to 'Worst Acne Ever'. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on objective acne in female participants | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in objective acne using the Global Evaluation Acne (GEA) scale (women only) will be summarized and compared between treatment arms. A score of 1 to 5 is given by the Investigator where 0 is 'Clear, no lesions', 1 is 'Almost clear. Almost no lesions', 2 is 'Mild', 3 is 'Moderate', 4 is 'Severe' and 5 is 'Very severe'. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on glycated hemoglobin (HbA1c) levels. | The change from screening to 4, 10, 16, 34, and 52 weeks of randomized treatment in HbA1c levels will be summarized and compared between treatment arms. | Screening to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on waist circumference. | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in waist circumference will be summarized and compared between treatment arms. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on body weight. | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in body weight will be summarized and compared between treatment arms. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on Quality of Life (QoL) using the self-completed Medical Outcome Study 36-Item Short Form Health Survey (SF-36®) total score and the sub domain of vitality. | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in QoL using the self completed SF-36® total score and the sub domain of vitality will be summarized and compared between treatment arms. The SF-36 measures eight scales: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). All components contribute in different proportions to the overall measures. Where the minimum score is 0 and maximum score is 100 and a high score is a more favorable score. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on QoL using the Multidimensional Assessment of Fatigue (MAF). | The MAF is a 16 item scale that measures fatigue according to four dimensions: degree and severity, distress that it causes, timing of fatigue, and its impact on various activities of daily living, with a range of score from 1 - 10 per item to give a Global Fatigue Score of up to 50 with a high score indicating a worse outcome. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To compare Chronocort to IRHC in terms of the impact on QoL using the EuroQol 5 level Standardized Health Questionnaire (EQ-5D-5L™). | The change from baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment in QoL using the EQ-5D-5L™ will be summarized and compared between treatment arms.The EQ-5D-5L is a self-assessed, QoL questionnaire. The scale measures on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Where the minimum score is 0 and maximum score is 100, a high score indicates a more favorable outcome. | Baseline to 4, 10, 16, 34, and 52 weeks of randomized treatment | 
| To assess compliance over the study period. | The percentage treatment compliance between visits and overall will be summarized | 52 weeks |