Congenital Adrenal Hyperplasia
Conditions
Keywords
Glucocorticoid therapy
Brief summary
This study is a parallel arm, randomised, open-label study, including dose titration and admissions for four overnight stays for 24-hour endocrine profiles. It will compare the efficacy, safety and tolerability of Chronocort® with standard glucocorticoid replacement therapy in the treatment of congenital adrenal hyperplasia (CAH) over a treatment period of 6 months. Dose titration decisions in both treatment groups will be made by a central independent physician, blinded to the treatment arm, using information generated from the 24-hour endocrine profiles. Each treatment arm will be subject to the same titration rules throughout the study, ensuring that opportunities for optimisation and control of androgens are the same in both groups.
Detailed description
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.
Interventions
DRUGChronocort®
Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.
DRUGstandard glucocorticoid therapy
Subjects in this arm will continue on their standard hydrocortisone therapy
Sponsors
Neurocrine UK Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 11 study sites in 7 countries: Denmark 1, France 2, Germany 1,Netherlands 1, Sweden 1, UK 4, and USA 1.
Pre-assignment details
Following written informed consent and screening tests (Visit 0), eligible participants were called back for the baseline visit. As part of the baseline assessment, participants were admitted overnight for a 24- hour endocrine profile whilst remaining on their standard therapy. Participants were then randomised to Chronocort or standard therapy.
Participants by arm
| Arm | Count |
|---|---|
| Chronocort® Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect.
Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol. | 61 |
| Standard Glucocorticoid Therapy Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of:
1. Hydrocortisone only
2. Prednisone or prednisolone, alone or in combination with hydrocortisone
3. Dexamethasone, alone or in combination with any other glucocorticoid | 61 |
| Total | 122 |
Baseline characteristics
| Characteristic | Chronocort® | Standard Glucocorticoid Therapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 61 Participants | 59 Participants | 120 Participants |
| Age, Continuous | 35.2 years | 37.5 years | 36.3 years |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 60 Participants | 60 Participants | 120 Participants |
| Region of Enrollment Europe | 57 participants | 57 participants | 114 participants |
| Region of Enrollment United States | 4 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 42 Participants | 36 Participants | 78 Participants |
| Sex: Female, Male Male | 19 Participants | 25 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 61 |
| other Total, other adverse events | 59 / 61 | 48 / 61 |
| serious Total, serious adverse events | 7 / 61 | 5 / 61 |
Outcome results
Primary
Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP
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).
Time frame: 24 weeks
Population: The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronocort® | Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP | -0.403 Z-score | Standard Deviation 0.8499 |
| Standard Glucocorticoid Therapy | Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP | -0.172 Z-score | Standard Deviation 0.7776 |
Comparison: The primary efficacy variable was the natural logarithm of the mean of the 24-hour SDS profile for the natural logarithm of 17-OHP. The SDS profile was calculated as the SDS of log transformed 17-OHP concentration unsigned. 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.p-value: =0.552195% CI: [-0.299, 0.161]ANCOVA
Secondary
17-OHP and A4 by Individual Baseline Treatment Strata.
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).
Time frame: 24 weeks
Population: The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronocort® | 17-OHP and A4 by Individual Baseline Treatment Strata. | -0.248 Z-score | Standard Deviation 0.7661 |
| Standard Glucocorticoid Therapy | 17-OHP and A4 by Individual Baseline Treatment Strata. | -0.061 Z-score | Standard Deviation 0.8051 |
| Pre-Baseline - Dexamethasone - 17-OHP | 17-OHP and A4 by Individual Baseline Treatment Strata. | -0.245 Z-score | Standard Deviation 0.8522 |
| Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP | 17-OHP and A4 by Individual Baseline Treatment Strata. | -0.431 Z-score | Standard Deviation 0.8727 |
| Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP | 17-OHP and A4 by Individual Baseline Treatment Strata. | -0.320 Z-score | Standard Deviation 0.7627 |
| Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP | 17-OHP and A4 by Individual Baseline Treatment Strata. | -0.565 Z-score | Standard Deviation 1.2343 |
| Pre-Baseline - Hydrocortisone - A4 | 17-OHP and A4 by Individual Baseline Treatment Strata. | -0.211 Z-score | Standard Deviation 0.7426 |
| Pre-Baseline - Prednisone/Prednisolone - A4 | 17-OHP and A4 by Individual Baseline Treatment Strata. | 0.100 Z-score | Standard Deviation 0.8339 |
| Pre-Baseline - Dexamethasone - A4 | 17-OHP and A4 by Individual Baseline Treatment Strata. | 0.368 Z-score | Standard Deviation 0.3521 |
| Pre-Baseline - Chronocort vs. Hydrocortisone - A4 | 17-OHP and A4 by Individual Baseline Treatment Strata. | 0.015 Z-score | Standard Deviation 1.0128 |
| Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 | 17-OHP and A4 by Individual Baseline Treatment Strata. | 0.328 Z-score | Standard Deviation 0.7256 |
| Pre-Baseline - Chronocort vs. Dexamethasone - A4 | 17-OHP and A4 by Individual Baseline Treatment Strata. | -0.092 Z-score | Standard Deviation 1.031 |
p-value: =0.818695% CI: [-0.354, 0.281]ANCOVA
p-value: =0.465595% CI: [-0.508, 0.237]ANCOVA
p-value: =0.908195% CI: [-1.32, 1.451]ANCOVA
p-value: =0.672995% CI: [-0.343, 0.527]ANCOVA
p-value: =0.532295% CI: [-0.257, 0.489]ANCOVA
p-value: =0.288595% CI: [-1.799, 0.662]ANCOVA
Secondary
Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4
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).
Time frame: 24 weeks
Population: The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronocort® | Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4 | 0.113 Z-score | Standard Deviation 0.9221 |
| Standard Glucocorticoid Therapy | Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4 | -0.041 Z-score | Standard Deviation 0.7731 |
Comparison: Change from Baseline to 24 Weeks in A4 Using an ANCOVA Model - The analysis conducted for the primary endpoint variable analysis of 17-OHP was repeated for A4.p-value: =0.740595% CI: [-0.234, 0.329]ANCOVA
Secondary
Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany.
Changes relative to Standard glucocorticoid therapy in body composition (DEXA - bone mineral density only) - measured at all sites except Germany.
Time frame: Baseline and 24 weeks
Population: The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. German subjects were excluded from this analysis subset.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronocort® | Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany. | -0.001 g/cm^2 | Standard Deviation 0.025 |
| Standard Glucocorticoid Therapy | Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany. | -0.008 g/cm^2 | Standard Deviation 0.0399 |
p-value: =0.261495% CI: [-0.007, 0.025]ANCOVA
Secondary
Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass)
Changes relative to Standard glucocorticoid therapy in body composition (DEXA) (fat mass and lean mass) - measured at all sites except Germany.
Time frame: Baseline and 24 weeks
Population: The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. German subjects were excluded from this analysis subset.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronocort® | Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) | -0.575 kilograms | Standard Deviation 3.2744 |
| Standard Glucocorticoid Therapy | Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) | 0.445 kilograms | Standard Deviation 2.466 |
| Pre-Baseline - Dexamethasone - 17-OHP | Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) | 0.640 kilograms | Standard Deviation 2.3304 |
| Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP | Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) | 0.234 kilograms | Standard Deviation 1.3689 |
Comparison: German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.p-value: =0.15695% CI: [-2.294, 0.374]ANCOVA
Comparison: German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.p-value: =0.339295% CI: [-0.455, 1.305]ANCOVA
Secondary
Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit
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.
Time frame: 24 weeks
Population: The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chronocort® | Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit | 30 Participants |
| Standard Glucocorticoid Therapy | Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit | 25 Participants |
| Pre-Baseline - Dexamethasone - 17-OHP | Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit | 30 Participants |
| Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP | Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit | 30 Participants |
p-value: =0.987795% CI: [0.45, 2.19]Regression, Logistic
p-value: =0.849895% CI: [0.43, 2.02]Regression, Logistic