Adrenal Insufficiency
Conditions
Brief summary
This study will investigate a new drug called Infacort®; a newly-developed immediate release formulation of a well-established drug called hydrocortisone. Hydrocortisone is used as a replacement treatment for people whose adrenal glands are not producing enough natural cortisol - a condition known as adrenal insufficiency. The study will assess how Infacort® acts once inside the body, by measuring cortisol and other hormone levels in the body, compared to already marketed hydrocortisone tablet and hydrocortisone intravenous (through the vein) injection. The population who are eligible to take part in the study are healthy male volunteers, aged between 18 and 60 years of age.
Detailed description
The study will evaluate the normal physiology, PK and metabolism of cortisol, investigate the PK and bioavailability of cortisol from the test Infacort® Granules (hydrocortisone) and the reference hydrocortisone tablets and i.v injection in healthy adult male volunteers and explore the role of cortisol in the regulation of metabolic pathways.
Interventions
DRUGHydrocortisone granules
Multi-particulate granules
DRUGHydrocortisone Tablet
Standard hydrocortisone tablets
DRUGi.v. Hydrocortisone Injection
Standard hydrocortisone solution for intravenous injection
OTHERDexamethasone
Challenge agent
Sponsors
Simbec Research
Neurocrine UK Limited
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male volunteers between 18 and 60 years of age, inclusive (at screening). * Subjects with a Body Mass Index (BMI) of 21-28. Body Mass Index = Body weight (kg) / (Height (m))\*2. * Subjects with no clinically significant abnormal serum biochemistry, haematology and urinalysis values within 14 days prior to Day 1 of Study Period 1. * Subjects with a negative urinary drugs of abuse screen, determined within 14 days prior to Day 1 of Study Period 1. A positive alcohol test may be repeated at the discretion of the Investigator. * Subjects with negative HIV and Hepatitis B and C results. * Subjects with no clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined within 14 days prior to Day 1 of Study Period 1. * Subjects with no clinically-significant deviation outside the normal ranges for blood pressure and pulse measurements. * Subjects (unless anatomically sterile or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) and sexual partners must use effective contraception methods during the trial and for 3 months after the last dose, for example: * Oral contraceptive + condom * Intra-uterine device (IUD) + condom * Diaphragm with spermicide + condom * Subjects must be available to complete the study. * Subjects must satisfy a medical examiner about their fitness to participate in the study. * Subjects must provide written informed consent to participate in the study.
Exclusion criteria
* A clinically significant history of gastrointestinal disorder likely to influence drug absorption. * Receipt of regular medication within 14 days prior to Day 1 of Study Period 1 (including high dose vitamins, dietary supplements or herbal remedies). * Receipt of any vaccination within 14 days prior to Day 1 of Study Period 1. * Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular or metabolic dysfunction. * Presence of clinically significant infections (systemic fungal and viral infections, acute bacterial infections). * Current or previous history of tuberculosis. * A clinically significant history of previous allergy / sensitivity to Hydrocortisone and/or Dexamethasone. * A clinically significant history or family history of psychiatric disorders/illnesses. * A clinically significant history of drug or alcohol abuse. * Inability to communicate well with the Investigator (i.e., language problem, poor mental development or impaired cerebral function). * Participation in a New Chemical Entity clinical study within the previous 4 months or a marketed drug clinical study within the previous 3 months. (N.B. The washout period between trials is defined as the period of time elapsed between the last dose of the previous study and the first dose of the next study) * Subjects who have consumed more than 2 units of alcohol per day within seven (7) days prior to Day 1 of Study Period 1or have consumed any alcohol within the 48 hour period prior to Day 1 of Study Period 1. * Donation of 450ml or more of blood within the previous 3 months. * Subjects who smoke (or ex-smokers who have smoked within 6 months prior to Day 1 of Study Period 1). * Subjects who work shifts (i.e. regularly alternate between days, afternoons and nights).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Serum Concentration (Cmax) | Hourly from 0 to 24 hours | Derived PK for Serum Cortisol: Maximum serum concentration (Cmax) |
| AUC0-t | Hourly from 0 to 24 hours | Derived PK for Serum Cortisol: Area under the curve from 0-24 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events (AEs) | Days 1-2 during each Study Period | Number of subjects with adverse events throughout the study. |
| Concentrations of Cortisol Binding Protein | Blood samples on Day 1 and/or Day 2 of each Study Period | Cortisol protein binding under physiological conditions and after the administration of dexamethasone and hydrocortisone. |
| Insulin Sensitivity Under Physiological Conditions and After Administration of Dexamethasone and Infacort®, Hydrocortisone Tablets and i.v Hydrocortisone. | Blood samples on Day 1 and/or Day 2 of each Study Period | A standardised mixed meal elevates blood glucose and provides a reproducible stimulation of insulin release. Lower levels of insulin secretion, whilst maintaining normoglycaemia would indicate enhanced insulin sensitivity and glucose disposal; higher insulin levels will reflect insulin resistance. |
| PK and Metabolism of Cortisol | Blood, urine & saliva samples on Day 1 and/or Day 2 of each Study Period | Blood: Serum cortisol under physiological conditions and after administration of dexamethasone and Infacort® Granules, Hydrocortisone Tablets and i.v Hydrocortisone Injection. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants received no IMP, dexamethasone (non-IMP), oral infacort, oral hydrocortisone, i.v. hydrocortisone | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 32.9 years STANDARD_DEVIATION 11.66 |
| Region of Enrollment United Kingdom | 14 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 14 | 3 / 14 | 0 / 14 | 1 / 14 | 2 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
AUC0-t
Derived PK for Serum Cortisol: Area under the curve from 0-24 hours
Time frame: Hourly from 0 to 24 hours
Population: All randomised subjects who received no IMP (no treatment), dexamethasone, oral Infacort®, hydrocortisone tablet and i.v. hydrocortisone, had sufficient serum cortisol concentration by time profiles and who did not violate the protocol
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Infacort® | AUC0-t | 2543.24 nmol*h/L | Standard Deviation 713.76 |
| Hydrocortisone Tablet | AUC0-t | 2896.73 nmol*h/L | Standard Deviation 850.31 |
| i.v Hydrocortisone Injection | AUC0-t | 2923.46 nmol*h/L | Standard Deviation 971.41 |
90% CI: [79.23, 95.52]
90% CI: [81.72, 99.04]
Primary
Maximum Serum Concentration (Cmax)
Derived PK for Serum Cortisol: Maximum serum concentration (Cmax)
Time frame: Hourly from 0 to 24 hours
Population: All randomised subjects who received no IMP (no treatment), dexamethasone, oral Infacort®, hydrocortisone tablet and i.v. hydrocortisone, had sufficient serum cortisol concentration by time profiles and who did not violate the protocol
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Infacort® | Maximum Serum Concentration (Cmax) | 940.012 nmol/L | Standard Deviation 283.773 |
| Hydrocortisone Tablet | Maximum Serum Concentration (Cmax) | 896.489 nmol/L | Standard Deviation 258.083 |
| i.v Hydrocortisone Injection | Maximum Serum Concentration (Cmax) | 1563.479 nmol/L | Standard Deviation 491.267 |
Comparison: Evaluation of Cmax90% CI: [54.69, 66.1]
90% CI: [96.92, 117.76]
Secondary
Adverse Events (AEs)
Number of subjects with adverse events throughout the study.
Time frame: Days 1-2 during each Study Period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infacort® | Adverse Events (AEs) | 3 participants |
| Hydrocortisone Tablet | Adverse Events (AEs) | 3 participants |
| i.v Hydrocortisone Injection | Adverse Events (AEs) | 0 participants |
| Hydrocortisone Tablet | Adverse Events (AEs) | 1 participants |
| i.v Hydrocortisone Injection | Adverse Events (AEs) | 2 participants |
Secondary
Concentrations of Cortisol Binding Protein
Cortisol protein binding under physiological conditions and after the administration of dexamethasone and hydrocortisone.
Time frame: Blood samples on Day 1 and/or Day 2 of each Study Period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infacort® | Concentrations of Cortisol Binding Protein | 22.950 ug/mL | Standard Deviation 2.7355 |
| Hydrocortisone Tablet | Concentrations of Cortisol Binding Protein | 23.441 ug/mL | Standard Deviation 3.0381 |
| i.v Hydrocortisone Injection | Concentrations of Cortisol Binding Protein | 22.386 ug/mL | Standard Deviation 2.8753 |
| Hydrocortisone Tablet | Concentrations of Cortisol Binding Protein | 21.757 ug/mL | Standard Deviation 3.6545 |
| i.v Hydrocortisone Injection | Concentrations of Cortisol Binding Protein | 21.482 ug/mL | Standard Deviation 3.2047 |
Secondary
Insulin Sensitivity Under Physiological Conditions and After Administration of Dexamethasone and Infacort®, Hydrocortisone Tablets and i.v Hydrocortisone.
A standardised mixed meal elevates blood glucose and provides a reproducible stimulation of insulin release. Lower levels of insulin secretion, whilst maintaining normoglycaemia would indicate enhanced insulin sensitivity and glucose disposal; higher insulin levels will reflect insulin resistance.
Time frame: Blood samples on Day 1 and/or Day 2 of each Study Period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infacort® | Insulin Sensitivity Under Physiological Conditions and After Administration of Dexamethasone and Infacort®, Hydrocortisone Tablets and i.v Hydrocortisone. | 70.529 uIU/mL | Standard Deviation 17.975 |
| Hydrocortisone Tablet | Insulin Sensitivity Under Physiological Conditions and After Administration of Dexamethasone and Infacort®, Hydrocortisone Tablets and i.v Hydrocortisone. | 80.668 uIU/mL | Standard Deviation 40.801 |
| i.v Hydrocortisone Injection | Insulin Sensitivity Under Physiological Conditions and After Administration of Dexamethasone and Infacort®, Hydrocortisone Tablets and i.v Hydrocortisone. | 77.575 uIU/mL | Standard Deviation 32.195 |
| Hydrocortisone Tablet | Insulin Sensitivity Under Physiological Conditions and After Administration of Dexamethasone and Infacort®, Hydrocortisone Tablets and i.v Hydrocortisone. | 70.650 uIU/mL | Standard Deviation 34.983 |
| i.v Hydrocortisone Injection | Insulin Sensitivity Under Physiological Conditions and After Administration of Dexamethasone and Infacort®, Hydrocortisone Tablets and i.v Hydrocortisone. | 70.121 uIU/mL | Standard Deviation 27.14 |
Secondary
PK and Metabolism of Cortisol
Blood: Serum cortisol under physiological conditions and after administration of dexamethasone and Infacort® Granules, Hydrocortisone Tablets and i.v Hydrocortisone Injection.
Time frame: Blood, urine & saliva samples on Day 1 and/or Day 2 of each Study Period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infacort® | PK and Metabolism of Cortisol | 447.355 nmol/L | Standard Deviation 77.005 |
| Hydrocortisone Tablet | PK and Metabolism of Cortisol | 19.349 nmol/L | Standard Deviation 9.567 |
| i.v Hydrocortisone Injection | PK and Metabolism of Cortisol | 963.134 nmol/L | Standard Deviation 283.376 |
| Hydrocortisone Tablet | PK and Metabolism of Cortisol | 893.077 nmol/L | Standard Deviation 259.73 |
| i.v Hydrocortisone Injection | PK and Metabolism of Cortisol | 1580.337 nmol/L | Standard Deviation 492.285 |