Comparison of Chronocort® With Standard Glucocorticoid Therapy in Patients With Congenital Adrenal Hyperplasia

At baseline, subjects will be admitted overnight for a 24-hour endocrine profile whilst on their standard therapy. Subjects will attend the study site in the morning and have 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) levels assessed at 15:00, 17:00, 19:00, 21:00, 23:00, 01:00, 03:00, 05:00, 07:00, 09:00, 11:00, 13:00 and 15:00. Safety laboratory tests, a DEXA scan for body composition, and height, weight and waist circumference will be recorded. Subjects will then be randomised to Chronocort® or to continue on their standard care. Randomisation will be stratified by baseline treatment:

1. hydrocortisone only or
2. prednisone or prednisolone, alone or in combination with hydrocortisone
3. dexamethasone only or in combination with any other glucorticoid

The initial dose setting at the start of the Chronocort® treatment will be based on hydrocortisone dose equivalent of baseline therapy in accordance with standard clinical practice. Further dose refinement/titration will be conducted in both treatment groups as necessary after 4 weeks and 12 weeks using a standardised titration algorithm after the subject has been re-admitted for further 24-hour endocrine profiles. Safety endpoints will also be measured at the 07:00 morning sample of each 24-hour profile assessment day. The decision to change doses in both treatment groups will be made by a central independent blinded physician, with the actual change in dose then being made by the local investigator looking after the subject. At 6 months, all the baseline tests will be repeated (including the 24-hour profile). All subjects may then continue on Chronocort®, whatever their randomised treatment, as part of an open-label extension study (to be conducted under a separate protocol). Stress doses of hydrocortisone will be given throughout the study for intercurrent illnesses as medically indicated according to "sick day rules".

• Chronocort® (Drug), also known as Hydrocortisone: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.
• standard glucocorticoid therapy (Drug), also known as hydrocortisone, prednisone, prednisolone, dexamethasone: Subjects in this arm will continue on their standard hydrocortisone therapy

Primary outcomes

• Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP [24 weeks]: Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for 17-OHP (17-Hydroxyprogesterone). The primary efficacy variable was the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of 17-OHP. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed 17-OHP values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of 17-OHP when compared to baseline (0).

Secondary outcomes

• Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4 [24 weeks]: Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for A4 (androstenedione). This secondary efficacy variable was calculated as follows: the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of A4. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed A4 values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of A4 when compared to baseline (0).
• 17-OHP and A4 by Individual Baseline Treatment Strata. [24 weeks]: 17-OHP and A4 by individual baseline treatment strata presented in the same manner as the primary endpoint (using 24-hour SDS profile at 24 weeks). Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for 17-OHP and A4. This secondary efficacy variable was calculated as follows: the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of 17-OHP and A4. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed 17-OHP and A4 values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of 17-OHP and A4 when compared to baseline (0).
• Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit [24 weeks]: 17-OHP and A4 levels at 09:00 at the week 24 visit, as a responder analysis (i.e. the number of participants achieving results in the optimal range). Optimal range for 17-OHP (male) = 1.2* - 6.7 nmol/L (female) = 1.2* - 8.6 Optimal range for A4 (male) = 1.4 - 5.2 nmol/L (female) = 1.0 - 7.0 nmol/L * = There is no lower reference range available for 17-OHP, hence the lower limit of the optimal range was used in the derivation of the average Standard Deviation Score. This enabled calculation of an 'unsigned' SDS score which was used to assess potential over-treatment as well as under-treatment.
• Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) [Baseline and 24 weeks]: Changes relative to Standard glucocorticoid therapy in body composition (DEXA) (fat mass and lean mass) - measured at all sites except Germany.
• Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany. [Baseline and 24 weeks]: Changes relative to Standard glucocorticoid therapy in body composition (DEXA - bone mineral density only) - measured at all sites except Germany.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Known CAH due to 21-hydroxylase deficiency (classic CAH) diagnosed in childhood with documented (at any time) elevated 17-OHP and/or A4 and currently treated with hydrocortisone, prednisone, prednisolone or dexamethasone (or a combination of the aforementioned glucocorticoids) on a stable glucocorticoid therapy for a minimum of 6 months.
2. Provision of signed written informed consent.
3. Non-pregnant, non-lactating females who are post menopausal, naturally or surgically sterile, or of childbearing potential with a negative urinary pregnancy test and using a medically acceptable method of contraception.
4. Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 3 months prior to screening, except in subjects who have been diagnosed with hypertension where the renin is not being used to monitor fludrocortisone replacement.
5. Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 3 months prior to screening, except in subjects who have been diagnosed with hypertension where the renin is not being used to monitor fludrocortisone replacement.

Exclusion Criteria:

1. Co-morbid condition requiring daily administration of a medication (or consumption of any material) 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 the ULN).
3. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH.
4. Subjects with any other significant medical or psychiatric conditions that in the opinion of the investigator would preclude participation in the trial.
5. History of malignancy (other than basal cell carcinoma successfully treated >6 months prior to entry into the study).
6. Participation in another clinical trial of an investigational or licensed drug or device within the 3 months prior to inclusion in this study.
7. Subjects with a history of bilateral adrenalectomy.
8. Subjects having previously been exposed to Chronocort®.
9. Subjects unable to comply with the requirements of the protocol.

Participant flow

Outcome results

• Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP (Primary), Mean, Z-score: Chronocort® -0.403 +/- 0.8499; Standard Glucocorticoid Therapy -0.172 +/- 0.7776 (p =0.5521)
• Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4 (Secondary), Mean, Z-score: Chronocort® 0.113 +/- 0.9221; Standard Glucocorticoid Therapy -0.041 +/- 0.7731 (p =0.7405)
• 17-OHP and A4 by Individual Baseline Treatment Strata. (Secondary), Mean, Z-score: Pre-Baseline - Hydrocortisone - 17-OHP -0.248 +/- 0.7661; Pre-Baseline - Prednisone/Prednisolone - 17-OHP -0.061 +/- 0.8051; Pre-Baseline - Dexamethasone - 17-OHP -0.245 +/- 0.8522; Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP -0.431 +/- 0.8727; Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP -0.320 +/- 0.7627; Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP -0.565 +/- 1.2343; Pre-Baseline - Hydrocortisone - A4 -0.211 +/- 0.7426; Pre-Baseline - Prednisone/Prednisolone - A4 0.100 +/- 0.8339; Pre-Baseline - Dexamethasone - A4 0.368 +/- 0.3521; Pre-Baseline - Chronocort vs. Hydrocortisone - A4 0.015 +/- 1.0128; Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 0.328 +/- 0.7256; Pre-Baseline - Chronocort vs. Dexamethasone - A4 -0.092 +/- 1.0310 (p =0.8186)
• Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit (Secondary), Count of participants, Participants: Chronocort - 09:00h Response - 17-OHP 30; Chronocort - 09:00h Response - A4 25; Standard Glucocorticoid Therapy - 09:00h Response - 17-OHP 30; Standard Glucocorticoid Therapy - 09:00h Response - A4 30 (p =0.9877)
• Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) (Secondary), Mean, kilograms: Chronocort - DEXA - Fat Mass -0.575 +/- 3.2744; Standard Glucocorticoid Therapy - DEXA - Fat Mass 0.445 +/- 2.4660; Chronocort - DEXA - Lean Mass 0.640 +/- 2.3304; Standard Glucocorticoid Therapy - DEXA - Lean Mass 0.234 +/- 1.3689 (p =0.156)
• Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany. (Secondary), Mean, g/cm^2: Chronocort - DEXA - Bone Mineral Density -0.001 +/- 0.0250; Standard Glucocorticoid Therapy - DEXA - Bone Mineral Density -0.008 +/- 0.0399 (p =0.2614)

Adverse events

Time frame: Adverse event information was collected from the point of enrolment to completion of the study (6 months).

Serious adverse events by term

Other adverse events by term

113 more terms not shown.

Limitations and caveats: A limitation of the pre-defined primary endpoint was that it included an unsigned SDS score over a 24-hour period.

• Results publication: 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. PMID 33527139

• Study Protocol (PDF, 2017-08-23)
• Statistical Analysis Plan (PDF, 2018-09-13)

• Debbie Merke, MD, Principal investigator, National Institutes of Health (NIH)