Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Chronocort · 8 trials · 5 indications
Biochemical response was defined as a participant who a) was in biochemical control at the 08:00 assessment and b) was receiving 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. Biochemical control was defined as both a 17-OHP concentration equal to or below the upper limit for optimal control (1200 ng/dL \[36.4 nmol/L\]) and an A4 concentration equal to or below the upper limit of the reference range (150 ng/dL \[5.2 nmol/L\] for men and 200 ng/dL \[7.0 nmol/L\] for women). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomization.
Over-replacement normally presents with chronic effects such as weight gain, increased appetite, sleeping difficulties, increased acne and Cushingoid syndrome.
Under-replacement normally presents with acute effects such as sudden weight loss, lack of appetite, nausea, vomiting, headache, blurred vision, fatigue, weakness, dizziness, light-headedness and syncope.
Use of Immediate Release Hydrocortisone (IRHC) from the emergency packs for stress dosing or use of any additional glucocorticoid treatment.
Occurrence of adrenal crises throughout the study.
The incidence, nature, severity, relatedness, duration, outcome, seriousness, and expectedness of treatment-emergent adverse events (TEAEs) throughout the study.
Lab parameters will be summarized and compared throughout the study as follows: Platelet count, Red blood cell count (RBC), Haemoglobin, Haematocrit, RBC Indices: Mean corpuscular volume (MCV), Mean cell haemoglobin (MCH). Mean cell haemoglobin concentration (MCHC), Red cell distribution width (RDW). White blood cell (WBC) count with differential (absolute and %): Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils.
To measure the change from pre-Chronocort baseline in terms of clinical chemistry safety laboratory assessments \[Safety and Tolerability\]. Blood urea nitrogen (BUN), Creatinine, Chloride, Total magnesium, Potassium, Sodium, Calcium, Total carbon dioxide (CO2), Inorganic phosphorus, AST/serum glutamic-oxaloacetic transaminase (SGOT), ALT/serum glutamic-pyruvic transaminase (SGPT), Alkaline phosphatase, Albumin, Total and direct bilirubin, Total protein, Lactate dehydrogenase (LDH), Total creatine kinase (CK), Uric acid.
Blood pressure measurements throughout the study will be summarised and compared.
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).
The primary efficacy outcome variable is the 07:00 hour serum cortisol level after 4 weeks of treatment. The treatment effect (Chronocort minus Plenadren, after logarithmic transformation) will be estimated in the efficacy evaluable analysis set (EEAS) (defined as participants with morning serum cortisol assessed at baseline and after each treatment period, with no major protocol violations) using a linear mixed model.
Comparing the area under the concentration time curve of Chronocort® compared to Cortef® immediate release hydrocortisone tablets.
Time at maximum concentration in serum
Maximum serum concentration
Area under the plasma concentration-time curve
Area under the plasma concentration-time curve from zero (0) hours to infinity (∞)
Drug clearance (CL) is defined as the volume of plasma in the vascular compartment cleared of drug per unit time
Tmax measures the time at which Cmax - maximum serum concentration - is observed
Tlag measures the delay between dosing and being able to observe the drug/metabolite within the sampling area (e.g., blood serum)
Cmax measures the time taken for the drug/metabolite to reach maximum serum concentration
Area under the serum concentration versus time curve from time
Area under the serum concentration versus time curve from time = 0h extrapolated to infinity
Time to drug clearance
Time required to reach 1/2 Cmax
| Arm | Type | Description |
|---|---|---|
| Chronocort | EXPERIMENTAL | Participants received Chronocort at a starting dose of 30 milligrams (mg), with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. |
| Cortef | ACTIVE_COMPARATOR | Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. |
| Chronocort (hydrocortisone modified-release capsule) | EXPERIMENTAL | Chronocort (hydrocortisone modified-release capsules) supplied as 5 mg and 10 mg per capsule for oral administration. |
| Chronocort® | EXPERIMENTAL | 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. |
| standard glucocorticoid therapy | ACTIVE_COMPARATOR | Subjects in this arm will continue previous oral glucocorticoid therapy titrated to effect. |
| Plenadren | ACTIVE_COMPARATOR | Plenadren (hydrocortisone modified-release tablet) supplied as 5 mg and 20 mg strengths and administered orally. Plenadren 25 mg will be taken on waking (typically between 06:00 and 08:00 hours). |
| Chronocort®, then Cortef® | EXPERIMENTAL | Single dose of 20mg Chronocort® (oral administration), followed by a single dose of 20mg Cortef® Immediate Release Hydrocortisone Tablets (oral administration). |
| Cortef®, then Chronocort® | ACTIVE_COMPARATOR | Single dose of 20mg Cortef® Immediate Release Hydrocortisone Tablets (oral administration), followed by a single dose of 20mg Chronocort® (oral administration). |
| Part A1 | EXPERIMENTAL | Three formulations of Chronocort 30mg were administered to healthy volunteers, with a 7-day washout period between each dose. Each treatment was administered in a randomised, crossover manner. |
| Part A2 | EXPERIMENTAL | Three additional formulations of Chronocort 30mg were administered to healthy volunteers, with a 7-day washout period between each dose. Each treatment was administered in a randomised, crossover manner. |
| Part B | EXPERIMENTAL | The best formulation of Chronocort was then selected from Parts A1 \& A2. This was then administered in four separate treatment periods, in dosages of 5mg, 10mg, 20mg and 30mg. Each treatment was administered in a randomised, crossover manner. |
| Group 1 | EXPERIMENTAL | Volunteers in group 1 received the following interventions: Chronocort® 30 mg given at night (\~ 23:00h) as a combination of one 10mg capsule and one 20mg capsule (n=18). Chronocort® 30mg given as one 20mg capsule at night (\~ 23:00h) and as one 10mg capsule in the morning (\~ 7:00h) following the initial night-time dose (n=18). Hydrocortisone 30mg given at night (\~ 23:00h) given as three 10mg tablets (n=18). Each administration of IMP was separated by a washout period of at least 7 days. |
| Group 2 | EXPERIMENTAL | Volunteers in group 2 received the following interventions: Chronocort® 5mg given at night (\~ 23:00h) as one 5mg capsule (n=12). Chronocort® 10mg given at night (\~ 23:00h) as one 10mg capsule (n=12). Chronocort® 20mg given at night (\~ 23:00h) as one 20mg capsule (n=12). Each administration of IMP was separated by a washout period of at least 7 days. |
| Cortef and Chronocort | EXPERIMENTAL | Cortef 3 times daily(total dose 30 mg)for minimum of 7 days followed by Chronocort 30 mg once daily nigh time dose for 28 +/- 3 days duration |
| Name | Type | Description |
|---|---|---|
| Chronocort | DRUG | Over-encapsulated hydrocortisone modified-release capsule for oral administration. |
| Cortef | DRUG | Over-encapsulated hydrocortisone immediate-release tablet for oral administration. |
| Placebo | OTHER | Matching placebo |
| Chronocort® | DRUG | 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 | Subjects in this arm will continue on their standard hydrocortisone therapy |
| Plenadren | DRUG | Hydrocortisone modified-release tablets for oral administration - 5mg and 20mg |
| Cortef® | DRUG | Single dose of 20mg Cortef® administered in one treatment period |
| Hydrocortisone | DRUG | Generic hydrocortisone |
Inclusion Criteria: * Male or female participants must be aged 16 years or older at the time of signing the informed consent/assent. * 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). * Participants with kn...
Chronocort is an investigational small molecule being developed for adrenal insufficiency, primary adrenal insufficiency, and congenital adrenal hyperplasia. It is a modified-release formulation of hydrocortisone intended as a replacement therapy for these endocrine conditions. Chronocort is still in clinical development and is not approved by the FDA.
Chronocort is being developed by Neurocrine Biosciences, Inc., a biopharmaceutical company traded on NASDAQ under the ticker NBIX. The company is conducting clinical trials to evaluate Chronocort as a treatment for adrenal insufficiency and related conditions.
Chronocort is in Phase 1 clinical development. It has completed five clinical trials, including Phase 1 and Phase 2 studies, with a total enrollment of 303 participants. Chronocort remains investigational and has not received FDA approval.
Chronocort has completed several clinical trials, including NCT03019614, a Phase 1 study comparing Chronocort to hydrocortisone in healthy volunteers with congenital adrenal hyperplasia and adrenal insufficiency. Other completed trials include NCT03051893, NCT03343327, and NCT05222152, which evaluated Chronocort in healthy subjects and adults with adrenal insufficiency.
Chronocort is a modified-release formulation of hydrocortisone, designed to provide a different pharmacokinetic profile. Clinical trials have compared Chronocort directly to hydrocortisone products such as Cortef and Plenadren to assess its absorption and effects in healthy volunteers and patients with adrenal insufficiency.