An Investigational Study of Hydrocortisone

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open Label, Partially Randomised, Single Dose, Crossover Study to Evaluate the PK, Oral Bioavailability and Relationship to Metabolic Parameters of Hydrocortisone and Infacort® in Healthy Adult Male Volunteers.

Conditions
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Adrenal Insufficiency

Intervention / Treatment
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* Drug: Hydrocortisone granules
* Drug: Hydrocortisone Tablet
* Drug: i.v. Hydrocortisone Injection
* Other: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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: 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Endogenous Cortisol<br>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. | |
| Other: Dexamethasone<br>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 | Other: Dexamethasone<br>* Challenge agent<br>* Other names: Non-IMP;|
| Experimental: Infacort®<br>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. | Drug: Hydrocortisone granules<br>* Multi-particulate granules<br>* Other names: Infacort;|
| Active Comparator: Hydrocortisone Tablet<br>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. | Drug: Hydrocortisone Tablet<br>* Standard hydrocortisone tablets<br>* Other names: Commerical supply;|
| Active Comparator: i.v Hydrocortisone Injection<br>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. | Drug: i.v. Hydrocortisone Injection<br>* Standard hydrocortisone solution for intravenous injection<br>* Other names: Commerical supply;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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 |