| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency |
|
| E.1.1.1 | Medical condition in easily understood language |
| Increase activity of the adrenal glands |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare Chronocort to immediate-release hydrocortisone replacement therapy (IRHC) in terms of biochemical responder rate after 52 weeks of randomized treatment. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare Chronocort to IRHC in terms of dose responder rate after 52 weeks of randomized treatment.
2. To compare Chronocort to IRHC in terms of total daily dose after 52 weeks of randomized treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be aged 16 years or older at the time of signing the informed consent/assent.
2. 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).
3. 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.
4. 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 baseline.
5. Male and female participants.
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 (Appendix 4), not breastfeeding, and at least one of the following conditions applies:
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4.
OR
A WOCBP with 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.
6. Capable of giving signed informed consent/assent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
|
| E.4 | Principal exclusion criteria |
1. 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).
2. History of bilateral adrenalectomy.
3. History of malignancy (other than basal cell carcinoma successfully treated >26 weeks prior to entry into the study).
4. Participants who have type 1 diabetes or receive regular insulin.
5. Persistent signs of adrenal insufficiency or the participant does not tolerate treatment at the end of the 4-week run-in period.
6. Participants with any other significant medical or psychiatric conditions that in the opinion of the Investigator would preclude participation in the study.
7. Participants on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH.
8. Co-morbid condition requiring daily administration of a medication or consumption of any material that interferes with the metabolism of glucocorticoids (examples provided at http://medicine.iupui.edu/clinpharm/ddis/clinical-table/).
9. Participants who are receiving <10 mg hydrocortisone dose at baseline or the hydrocortisone dose equivalent.
10. Participants anticipating regular prophylactic use of additional steroids e.g. for strenuous exercise.
11. Participation in another clinical study of an investigational or licensed drug or device within the 12 weeks prior to screening.
12. 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.
13. Participants who have previously been exposed to Chronocort in any Diurnal study.
14. Participants who routinely work night shifts and so do not sleep during the usual night-time hours.
15. Participants, who in the opinion of the Investigator, will be unable to comply with the requirements of the protocol.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy outcome variable is whether or not the participant is a biochemical responder after 52 weeks of randomized treatment.
A biochemical responder is a participant who:
i) is in biochemical control at the 08:00 hours assessment after 52 weeks of randomized treatment (where in biochemical control is defined as both a 17-OHP concentration equal to or below the upper limit for optimal control and an A4 concentration equal to or below the upper limit of the reference range), and
ii) is 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).
The primary null hypothesis is that the response rate in the Chronocort arm is worse than or equal to the response rate in the IRHC arm minus 10 percentage points.
The primary alternate hypothesis is that the response rate in the Chronocort arm is better than the response rate in the IRHC arm minus 10 percentage points.
Biochemical non-inferiority of Chronocort to IRHC will be declared if the 95% CI for the difference in response rates between the 2 treatment arms (Chronocort minus IRHC) is wholly above minus 10 percentage points. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1st key secondary -
Whether or not the participant is a dose responder after 52 weeks of randomized treatment.
A dose responder is a participant who:
i) is receiving after 52 weeks of randomized treatment a total daily dose of hydrocortisone of not more than 25 mg, and
ii) is in biochemical control at the 08:00 hours assessment after 52 weeks of randomized treatment (where in biochemical control is defined as both a 17-OHP concentration equal to or below the upper limit for optimal control and an A4 concentration equal to or below the upper limit of the reference range).
The difference (Chronocort minus IRHC) between the proportion of participants in each treatment arm who are dose responders 52 weeks after randomization will be estimated in the FAS. Participants who die or withdraw from treatment before 52 weeks will be classified as not a dose responder. Participants receiving rescue medication under the 'stress dosing rules' within 5 days before the scheduled visit at 52 weeks after randomization will have their visit delayed appropriately1.
Dose superiority of Chronocort to IRHC will be declared if the 95% CI for the difference in proportions lies wholly above zero, provided that biochemical non-inferiority of Chronocort to IRHC has been declared under the primary efficacy objective.
The first key secondary null hypothesis is that the response rate in the Chronocort arm is worse than or equal to the response rate in the IRHC arm.
The 2nd key secondary -
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 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.
The second key secondary null hypothesis is that the mean total daily dose after 52 weeks of randomized treatment in the Chronocort arm is higher than or equal to the mean total daily dose after 52 weeks of randomized treatment in the IRHC arm. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Turkey |
| Japan |
| United States |
| France |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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