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

The study will compare the efficacy, safety and tolerability of twice daily Chronocort with twice daily immediate release hydrocortisone replacement therapy (IRHC) (Cortef®) in participants aged 16 years and over with known classic Congenital Adrenal Hyperplasia (CAH) due to 21 hydroxylase deficiency.

• Chronocort (Drug), also known as Hydrocortisone modified-release: Over-encapsulated hydrocortisone modified-release capsule for oral administration.
• Cortef (Drug), also known as Immediate-release hydrocortisone, IRHC: Over-encapsulated hydrocortisone immediate-release tablet for oral administration.
• Placebo (Other): Matching placebo

Primary outcomes

• Percentage of Participants Who Were Biochemical Responders at Week 28 [Week 28]: Biochemical response was defined as a participant who a) was in biochemical control at the 08:00 assessment and b) was receiving 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. Biochemical control was defined as both a 17-OHP concentration equal to or below the upper limit for optimal control (1200 ng/dL \[36.4 nmol/L\]) and an A4 concentration equal to or below the upper limit of the reference range (150 ng/dL \[5.2 nmol/L\] for men and 200 ng/dL \[7.0 nmol/L\] for women). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.

Secondary outcomes

• Percentage of Participants Who Were Dose Responders at Week 28 [Week 28]: Dose response was defined as a participant who a) was receiving a total daily dose of hydrocortisone of not more than 25 mg and b) was in biochemical control at the 08:00 assessment. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Total Daily Dose of Hydrocortisone at Week 28 [Week 28]: Least squares (LS) mean was assessed using mixed model repeated measures (MMRM). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Number of Participants in Biochemical Control [Baseline and Week 28]: Biochemical control was defined as both a 17-OHP concentration (assessed at 08:00) equal to or below the upper limit for optimal control (1200 ng/dL \[36.4 nmol/L\]) and an A4 concentration equal to or below the upper limit of the reference range (150 ng/dL \[5.2 nmol/L\] for men and 200 ng/dL \[7.0 nmol/L\] for women). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline in Mean of 08:00 and 13:00 17-OHP Levels at Week 28 [Baseline, Week 28]: LS mean was assessed using analysis of covariance (ANCOVA). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline in Mean of 08:00 and 13:00 A4 Levels at Week 28 [Baseline, Week 28]: LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Number of Participants With Menstrual Regularity (Females of Childbearing Potential Only) at Week 28 [Week 28]: Data are presented for the number of participants with more than monthly menstrual cycles, monthly menstrual cycles, and number of participants with oligomenorrhoea and amenorrhoea. Oligomenorrhoea was defined as fewer than 9 menstrual cycles per year or cycle length >35 days and amenorrhoea as absent menses for ≥ 3 months. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline in Luteinizing Hormone Levels (Males Only) at Week 28 [Baseline, Week 28]: LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Percent Change From Baseline in Size of Testicular Adrenal Rest Tumors at Week 28 (Males Only) [Week 28]: Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline in Hirsutism at Week 28 Using the Ferriman-Gallwey Score (Females Only) at Week 28 [Baseline, Week 28]: Ferriman-Gallwey score is a method used to assess and quantify hirsutism in women. A total score < 8 is considered normal whereas a score of 8 to 15 indicates mild hirsutism. A score >15 indicates moderate or severe hirsutism. The Ferriman-Gallwey score ranged from 0 to 36. Higher score indicated more hirsutism. Change from baseline is reported (negative change from baseline indicated improvement). LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline in Acne Using the Global Evaluation Acne (GEA) Scale (Females Only) at Week 28 [Baseline, Week 28]: Acne severity was assessed according to GEA scale, which ranged from 0 (Clear. No lesions) to 5 (Very severe). Higher score indicated higher severity of acne. Change from baseline is reported (negative change from baseline indicated improvement). LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline in Glycated Hemoglobin (HbA1c) Percent Levels at Week 28 [Baseline, Week 28]: LS mean was assessed by ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline in Waist Circumference at Week 28 [Baseline, Week 28]: LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline in Body Weight at Week 28 [Baseline, Week 28]: LS mean was assessed by ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
• Change From Baseline Quality of Life Using the Self-completed Medical Outcome Study 36-Item Short Form Health Survey (SF-36) Total Score for the Physical and Mental Components and the Sub-domain of Vitality at Week 28 [Baseline, Week 28]: SF-36 evaluates aspects of functional health and well-being. The physical component has 4 sub-scales: physical function, role limitations due to physical problems, pain, and general health perception; and the mental component has 4 sub-scales: vitality, social function, role limitations due to emotional problems, and mental health. Total scores for the physical and mental component are presented as well as the sub-scale score for vitality. Scores were summarized and transformed into a range from 0 to 100; 0=worst, and 100=best outcome. Higher scores indicated better outcome. Change from baseline is reported (positive change from baseline indicated improvement). LS mean was assessed by ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.

Sex: All, ages: 16 Years to any

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.

Participant flow

Outcome results

• Percentage of Participants Who Were Biochemical Responders at Week 28 (Primary), Number, percentage of participants: Chronocort 40.0; Cortef 14.3 (p 0.0003)
• Percentage of Participants Who Were Dose Responders at Week 28 (Secondary), Number, percentage of participants: Chronocort 36.0; Cortef 10.7 (p 0.012)
• Total Daily Dose of Hydrocortisone at Week 28 (Secondary), Least squares mean, mg: Chronocort 20.2 (17.8 to 22.6); Cortef 26.0 (23.7 to 28.3) (p 0.0005)
• Number of Participants in Biochemical Control (Secondary), Count of participants, Participants: Chronocort 13; Cortef 8
• Change From Baseline in Mean of 08:00 and 13:00 17-OHP Levels at Week 28 (Secondary), Least squares mean, ng/dL: Chronocort -1223.91 (-2897.42 to 449.6); Cortef 1612.17 (-61.34 to 3285.68)
• Change From Baseline in Mean of 08:00 and 13:00 A4 Levels at Week 28 (Secondary), Least squares mean, ng/dL: Chronocort -4.85 (-115.57 to 105.86); Cortef 146.13 (35.42 to 256.85)
• Number of Participants With Menstrual Regularity (Females of Childbearing Potential Only) at Week 28 (Secondary), Count of participants, Participants: Chronocort 0; Cortef 0
• Change From Baseline in Luteinizing Hormone Levels (Males Only) at Week 28 (Secondary), Least squares mean, mIU/mL: Chronocort 0.15 (-0.71 to 1.02); Cortef -1.19 (-2.01 to -0.37)
• Percent Change From Baseline in Size of Testicular Adrenal Rest Tumors at Week 28 (Males Only) (Secondary), Mean, percent change: Chronocort -7.67 +/- 9.220; Cortef -0.90 +/- 1.810
• Change From Baseline in Hirsutism at Week 28 Using the Ferriman-Gallwey Score (Females Only) at Week 28 (Secondary), Least squares mean, score on a scale: Chronocort -1.0 (-2.5 to 0.6); Cortef -1.2 (-3.0 to 0.5)
• Change From Baseline in Acne Using the Global Evaluation Acne (GEA) Scale (Females Only) at Week 28 (Secondary), Least squares mean, score on a scale: Chronocort -0.3 (-0.5 to -0.1); Cortef -0.2 (-0.4 to 0.0)
• Change From Baseline in Glycated Hemoglobin (HbA1c) Percent Levels at Week 28 (Secondary), Least squares mean, percent HbA1c: Chronocort -0.01 (-0.09 to 0.06); Cortef -0.06 (-0.13 to 0.01)
• Change From Baseline in Waist Circumference at Week 28 (Secondary), Least squares mean, centimeters: Chronocort 0.867 (-1.387 to 3.121); Cortef -1.242 (-3.496 to 1.012)
• Change From Baseline in Body Weight at Week 28 (Secondary), Least squares mean, kilograms: Chronocort 1.29 (0.00 to 2.58); Cortef -1.67 (-2.96 to -0.38)
• Change From Baseline Quality of Life Using the Self-completed Medical Outcome Study 36-Item Short Form Health Survey (SF-36) Total Score for the Physical and Mental Components and the Sub-domain of Vitality at Week 28 (Secondary), Least squares mean, score on a scale: Chronocort -3.313 (-5.801 to -0.824); Cortef -1.031 (-3.976 to 1.913)

Adverse events

Time frame: Up to 30 days after last study dose (maximum treatment duration of approximately 53 weeks; median exposure = 255.0 days for Chronocort and 230.5 days for Cortef)

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2023-10-30)
• Statistical Analysis Plan (PDF, 2024-02-22)

• Principal Investigator, Principal investigator, Immedica Pharma AB