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".

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.