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| Name | Class |
|---|---|
| Simbec Research | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Endogenous Cortisol | No Intervention | No Study medication will be given during this study period, however various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. | |
| Dexamethasone | Other | 1mg Dexamethasone will be administered at 22:00 on Day 1 and at 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. Dexamethasone is considered a challenge agent and therefore a non-IMP |
|
| Infacort® | Experimental | 20mg Infacort® will be administered on Day 2 at 07:00. Dexamethasone is a challenge agent and will be taken to suppress endogenous adrenocorticotropic Hormone (ACTH) and cortisol. 1mg Dexamethasone will be administered at 22:00 on Day 1 and 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. |
|
| Hydrocortisone Tablet | Active Comparator | 20mg Hydrocortisone Tablet will be administered on Day 2 at 07:00. Dexamethasone is a challenge agent and will be taken to suppress endogenous ACTH and Cortisol. 1mg Dexamethasone will be administered at 22:00 on Day 1 and 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hydrocortisone granules | Drug | Multi-particulate granules |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Serum Concentration (Cmax) | Derived PK for Serum Cortisol: Maximum serum concentration (Cmax) | Hourly from 0 to 24 hours |
| AUC0-t | Derived PK for Serum Cortisol: Area under the curve from 0-24 hours | Hourly from 0 to 24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events (AEs) | Number of subjects with adverse events throughout the study. | Days 1-2 during each Study Period |
| Concentrations of Cortisol Binding Protein | Cortisol protein binding under physiological conditions and after the administration of dexamethasone and hydrocortisone. |
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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:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Girish Sharma | Simbec Research | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Simbec Research Limited | Merthyr Tydfil | CF48 4DR | United Kingdom |
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| ID | Title | Description |
|---|---|---|
| FG000 | 5-period Crossover | Study Period 1 (Endogenous Cortisol): No IMP was administered. Subjects were observed over a 24 hour period, during which sleep disruption was minimised, to record their endogenous cortisol production as a baseline figure and to confirm eligibility for the subsequent study periods. Study Period 2 (Dexamethasone): Subjects were admitted to the unit following a final confirmation of eligibility, prior to administration with Dexamethasone. Study Periods 3 and 4 (Infacort Granules or Hydrocortisone Tablets): Subjects were admitted to the unit and ongoing eligibility was confirmed. Subjects received both treatments (1 in Period 3, and 1 in Period 4), and were randomised using the PROC PLAN procedure of SAS. Subjects received Dexamethasone 1 hour prior to IMP administration. Study Period 5 (I.V. Hydrocortisone Injection): Subjects were admitted to the unit and ongoing eligibility was confirmed. Subjects received Dexamethasone 1 hour prior to IMP administration. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Healthy volunteers
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | All participants received no IMP, dexamethasone (non-IMP), oral infacort, oral hydrocortisone, i.v. hydrocortisone |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Serum Concentration (Cmax) | Derived PK for Serum Cortisol: Maximum serum concentration (Cmax) | 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 | Posted | Geometric Mean | Standard Deviation | nmol/L | Hourly from 0 to 24 hours |
|
8 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Endogenous Cortisol | No Study medication will be given during this study period, however various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | MedDRA (12.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr John Porter | Diurnal Limited | 02920 682069 | info@diurnal.com |
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| ID | Term |
|---|---|
| D000309 | Adrenal Insufficiency |
| ID | Term |
|---|---|
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D006854 | Hydrocortisone |
| D003907 | Dexamethasone |
| ID | Term |
|---|---|
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 |
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|
| i.v Hydrocortisone Injection | Active Comparator | 20mg i.v. Hydrocortisone Injection will be administered on Day 2 at 07:00. Dexamethasone is a challenge agent and will be taken to suppress endogenous ACTH and Cortisol. 1mg Dexamethasone will be administered at 22:00 on Day 1 and 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. |
|
| Hydrocortisone Tablet | Drug | Standard hydrocortisone tablets |
|
|
| i.v. Hydrocortisone Injection | Drug | Standard hydrocortisone solution for intravenous injection |
|
|
| Dexamethasone | Other | Challenge agent |
|
|
| Blood samples on Day 1 and/or Day 2 of each Study Period |
| 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. | Blood samples on Day 1 and/or Day 2 of each Study Period |
| 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. | Blood, urine & saliva samples on Day 1 and/or Day 2 of each Study Period |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Hydrocortisone Tablet | 20mg Hydrocortisone Tablet will be administered on Day 2 at 07:00. Dexamethasone is a challenge agent and will be taken to suppress endogenous ACTH and Cortisol. 1mg Dexamethasone will be administered at 22:00 on Day 1 and 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. Hydrocortisone Tablet |
| OG002 | i.v Hydrocortisone Injection | 20mg i.v. Hydrocortisone Injection will be administered on Day 2 at 07:00. Dexamethasone is a challenge agent and will be taken to suppress endogenous ACTH and Cortisol. 1mg Dexamethasone will be administered at 22:00 on Day 1 and 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. i.v. Hydrocortisone Injection |
|
|
|
| Secondary | Adverse Events (AEs) | Number of subjects with adverse events throughout the study. | Posted | Number | participants | Days 1-2 during each Study Period |
|
|
|
| Secondary | Concentrations of Cortisol Binding Protein | Cortisol protein binding under physiological conditions and after the administration of dexamethasone and hydrocortisone. | Posted | Mean | Standard Deviation | ug/mL | Blood samples on Day 1 and/or Day 2 of each Study Period |
|
|
|
| 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. | Posted | Mean | Standard Deviation | uIU/mL | Blood samples on Day 1 and/or Day 2 of each Study Period |
|
|
|
| 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. | Posted | Mean | Standard Deviation | nmol/L | Blood, urine & saliva samples on Day 1 and/or Day 2 of each Study Period |
|
|
|
| Primary | AUC0-t | Derived PK for Serum Cortisol: Area under the curve from 0-24 hours | 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 | Posted | Geometric Mean | Standard Deviation | nmol*h/L | Hourly from 0 to 24 hours |
|
|
|
|
| 0 |
| 14 |
| 3 |
| 14 |
| EG001 | Dexamethasone | 1mg Dexamethasone will be administered at 22:00 on Day 1 and at 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. Dexamethasone | 0 | 14 | 3 | 14 |
| EG002 | Infacort® | 20mg Infacort® will be administered on Day 2 at 07:00. Dexamethasone is a challenge agent and will be taken to suppress endogenous Adrenocorticotropic Hormone(ACTH)and Cortisol. 1mg Dexamethasone will be administered at 22:00 on Day 1 and 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. Infacort | 0 | 14 | 0 | 14 |
| EG003 | Hydrocortisone Tablet | 20mg Hydrocortisone Tablet will be administered on Day 2 at 07:00. Dexamethasone is a challenge agent and will be taken to suppress endogenous ACTH and Cortisol. 1mg Dexamethasone will be administered at 22:00 on Day 1 and 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. Hydrocortisone Tablet | 0 | 14 | 1 | 14 |
| EG004 | i.v Hydrocortisone Injection | 20mg i.v. Hydrocortisone Injection will be administered on Day 2 at 07:00. Dexamethasone is a challenge agent and will be taken to suppress endogenous ACTH and Cortisol. 1mg Dexamethasone will be administered at 22:00 on Day 1 and 06:00 and 12:00 on Day 2. Various blood, urine and saliva samples will be taken in order to measure normal levels of hormones and other chemicals at several time-points. i.v. Hydrocortisone Injection | 0 | 14 | 2 | 14 |
| Pyrexia | General disorders | MedDRA (12.0) | Non-systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA (12.0) | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (12.0) | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (12.0) | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (12.0) | Non-systematic Assessment |
|
| Mood swings | Psychiatric disorders | MedDRA (12.0) | Non-systematic Assessment |
|
The investigator must obtain written consent from the Sponsor prior to any publication of results.
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D013259 | Steroids, Fluorinated |
| Mean Difference (Final Values) |
| 89.96 |
| 2-Sided |
| 90 |
| 81.72 |
| 99.04 |
| Superiority or Other (legacy) |