E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital adrenal hyperplasia (CAH); is generally due to 21-hydroxylase deficiency, is a disease of the adrenal cortex characterised by cortisol deficiency with or without aldosterone deficiency, and androgen excess. Subjects with CAH are at risk of developing a number of clinical manifestations, such as obesity in children, insulin resistance, and polycystic ovaries, which may contribute to infertility in women with CAH. Oligomenorrhoea or amenorrhoea may be present in adolescence. |
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E.1.1.1 | Medical condition in easily understood language |
CAH is a group of inherited conditions that are present at birth where the body is missing a chemical substance that allows the adrenal glands to release the cortisol hormone. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010323 |
E.1.2 | Term | Congenital adrenal hyperplasia |
E.1.2 | System Organ Class | 100000004850 |
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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 assess safety and tolerability of Chronocort® over time, as assessed by signs and symptoms of adrenal insufficiency or over-treatment, use of sick day rules, adrenal crisis, adverse events (AEs), laboratory measures and clinical observation. |
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E.2.2 | Secondary objectives of the trial |
The long-term efficacy of Chronocort® will be assessed over time by the measurement of:
1. Total daily dose in mg/day of hydrocortisone &BSA during the study and the incidence of dose titrations
2. 17-hydroxyprogesterone (17-OHP) and androstenedione (A4),
measured at two time points (at 09:00 and 13:00 hours) for:
a. Disease control at each visit as assessed by both 17-OHP and A4 levels
in the optimal and normal range &by the proportion of dose given at
night.
b. 17-OHP and A4 standard deviation scores
c. Change in absolute values compared to pre-Chronocort® baseline
values
3. Changes compared to pCB baseline in:
a. Bone turnover markers - serum C-terminal cross-linked telopeptide,
osteocalcin
b. Testosterone
c. Fasting insulin and blood glucose levels and glycated haemoglobin
d. High sensitivity c-reactive protein and plasma renin activity
e. Body composition (dual energy X-ray absorptiometry)
f. Quality of life – SF-36®, Multidimensional Assessment of Fatigue, EQ-5D™ |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects with congenital adrenal hyperplasia (CAH) who have successfully completed the DIUR-003 or DIUR-005 clinical trials with the current formulation of Chronocort®
2. Provision of signed written informed consent. |
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E.4 | Principal 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. History of malignancy (other than basal cell carcinoma successfully treated >6 months prior to entry into the study)
5. Participation in another clinical trial of an investigational or licensed drug or device within the 3 months prior to inclusion in this study
6. Subjects with a history of bilateral adrenalectomy
7. Subjects unable to comply with the requirements of the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the safety of Chronocort® over time, assessed using but not limited to the following endpoints throughout the study:
1. Signs and symptoms of adrenal insufficiency or over-treatment
2. Use of sick day rules
3. Occurrence of adrenal crises
4. Occurrence of AEs
5. Change from pre-Chronocort® baseline in safety laboratory assessments at each visit
6. Change from pre-Chronocort® baseline in vital signs, weight, body mass index, and waist circumference at each visit. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Each visit throughout the study |
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E.5.2 | Secondary end point(s) |
The following secondary endpoints will be assessed (seeking to assess long term efficacy):
1. Total daily dose of Chronocort® in mg/day of hydrocortisone
2. Disease control throughout the study as assessed by both 17-OHP and A4 levels in the optimal and normal range, respectively
3. Change from pre-Chronocort® baseline at each visit in SDS of 17-OHP and A4 and the mean of the two timepoints
4. Change from pre-Chronocort® baseline at each visit in the absolute values of 17-OHP and A4
5. Change from pre-Chronocort® baseline at each visit in:
a. Bone turnover markers - CTX, osteocalcin
b. Testosterone (total)
c. Fasting insulin and blood glucose levels, and HbA1c
d. hsCRP and PRA
g. Body composition (DEXA)(fat mass, lean mass and total bone density)
e. Quality of life – SF-36®, MAF, EQ-5D™
6. Incidence of dose titrations. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At all visits:
1. Measurement of 17-OHP and A4 at two time points (the first at 09:00 and the second at 13:00 hours).
At baseline, at each 6-monthly visit and at the final visit:
1. Physical examination, vital signs, weight, BMI and waist circumference.
2. Safety blood tests, serum CTX, osteocalcin, PRA, hsCRP, HbA1c, testosterone,
fasting insulin and blood glucose levels.
3. Quality of life – SF-36®, MAF, EQ-5D™
At yearly intervals:
1. Body composition (DEXA)(fat mass, lean mass and total bone density) (also taken at baseline for subjects entering from study DIUR-003). |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
France |
Germany |
Sweden |
United Kingdom |
United States |
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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
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The final telephone call - 30 days after the last visit - of the last subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |