An Investigational Study of Hydrocortisone

This study has been completed.
Sponsor:
Collaborator:
Simbec Research
Information provided by (Responsible Party):
Diurnal Limited
ClinicalTrials.gov Identifier:
NCT01960530
First received: October 6, 2013
Last updated: January 6, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Adrenal Insufficiency
Drug: Infacort
Drug: Hydrocortisone Tablet
Drug: i.v. Hydrocortisone Injection
Other: Dexamethasone
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Official Title: A Single Centre, Open Label, Partially Randomised, Single Dose, Crossover Study to Build a Model of Hydrocortisone Metabolism and Evaluate the Pharmacokinetics, Oral Bioavailability and Relationship to Metabolic Parameters of Hydrocortisone and Infacort® in Healthy Adult Male Volunteers.

Resource links provided by NLM:


Further study details as provided by Diurnal Limited:

Primary Outcome Measures:
  • To determine the absolute bioavailability of cortisol from Infacort® Granules and Hydrocortisone Tablets using Intra-Venous (i.v) Hydrocortisone as the reference Injection. [ Time Frame: Blood samples on Day 1 and/or Day 2 of each Study Period ] [ Designated as safety issue: No ]

    Derived PK for Serum Cortisol:

    Non-compartmental Analysis - All Study Periods: Maximum serum concentration (Cmax), time to Cmax (tmax), elimination rate constant (λz), terminal elimination half life (t½), area under the concentration-time curve (AUC) from the time of dosing to the time of the last observed concentration (AUC0-t last) and extrapolated to infinity (AUC0-inf), area under the first moment curve (AUMC), clearance (CL/F), mean residence time (MRT) and mean absorption time (MAT)

    Compartmental Analysis - i.v Hydrocortisone Injection: beta t½, AUC, CL/F, MRT, volume of distribution (Vd) at steady state (Vss/Vdss), of the central compartment (Vc) and during the elimination phase (Vz/Vd area).

    Compartmental Analysis - Infacort® Granules & Hydrocortisone Tablets: Cmax, tmax, t½, AUC, MRT, AUMC, and MAT.


  • To determine the comparative bioavailability of cortisol from Infacort® Granules with the reference Hydrocortisone Tablets. [ Time Frame: Blood samples on Day 1 and/or Day 2 of each Study Period ] [ Designated as safety issue: No ]
    Following logarithmic transformation of Cmax, AUC0-t and AUC0-∞ cortisol values, data from periods 3, 4 and 5 data will be subjected to a mixed effects analysis of variance (ANOVA) including a fixed effect for treatment and a random effect for subject. Point estimates and 90% confidence intervals will be constructed for the contrasts between treatments using the residual mean square error obtained from the ANOVA. The point and interval estimates will then be back-transformed to give estimates of the ratios of the geometric least squares means and corresponding 90% confidence intervals. In addition, estimated geometric means and will be produced for each treatment group.


Secondary Outcome Measures:
  • To assess the safety and tolerability of Infacort Granules and hydrocortisone throughout the study. [ Time Frame: Days 1-2 during each Study Period ] [ Designated as safety issue: No ]
    Adverse events (AEs), routine laboratory assessments (haematology, biochemistry and urinalysis), vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate and oral body temperature) and 12-lead ECG (heart rate, PR interval, QRS duration, QT interval and QTcB interval).

  • To evaluate the concentrations of cortisol binding protein and its relationship to calculated free cortisol and cortisol plasma/saliva ratios 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 ] [ Designated as safety issue: No ]

    Cortisol Protein Binding: Serum ALB, CBG and Free cortisol.

    Free Cortisol Index: The measurement of serum cortisol will also be used to calculate the free cortisol index (FCI). This will be calculated as:

    Total Cortisol = CFree + CALB + CCBG

    Where CFree = free cortisol, CALB = cortisol bound to ALB and CCBG = cortisol bound to CBG.


  • To evaluate the normal physiology of cortisol and the relationship between cortisol and insulin sensitivity under physiological conditions and after administration of dexamethasone and Infacort®, Hydrocortisone Tablets and i.v Hydrocortisone. [ Time Frame: Blood samples on Day 1 and/or Day 2 of each Study Period ] [ Designated as safety issue: No ]
    A standardised mixed meal elevates blood glucose and provides a reproducible stimulation of insulin release. Assessment of the response will be determined by calculation of Cmax and AUC0-4 of glucose and insulin in the 4 hours following ingestion of the mixed meal. Comparison will be made of both the Cmax as well as AUC across the differing interventions. Lower levels of insulin secretion, whilst maintaining normoglycaemia would indicate enhanced insulin sensitivity and glucose disposal; higher insulin levels will reflect insulin resistance.

  • To evaluate the pharmacokinetics (PK) and metabolism of 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 ] [ Designated as safety issue: No ]

    Blood: Serum cortisol (same data as collected for derived PK calculations), cortisone.

    Saliva: Salivary cortisol Urine: Urinary steroid metabolites.


  • To explore the role of cortisol in regulation of metabolic pathways. [ Time Frame: Blood samples on Day 1 and/or Day 2 of each Study Period ] [ Designated as safety issue: No ]
    Exploratory Investigation: Plasma metabolome


Enrollment: 14
Study Start Date: October 2013
Study Completion Date: November 2013
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: 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.
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.
Other: Dexamethasone
Experimental: 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.
Drug: Infacort
Active Comparator: 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.
Drug: Hydrocortisone Tablet
Active Comparator: 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.
Drug: i.v. Hydrocortisone Injection

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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01960530

Locations
United Kingdom
Simbec Research Limited
Merthyr Tydfil, United Kingdom, CF48 4DR
Sponsors and Collaborators
Diurnal Limited
Simbec Research
  More Information

Additional Information:
No publications provided

Responsible Party: Diurnal Limited
ClinicalTrials.gov Identifier: NCT01960530     History of Changes
Other Study ID Numbers: Infacort 002
Study First Received: October 6, 2013
Last Updated: January 6, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Adrenal Insufficiency
Adrenal Gland Diseases
Endocrine System Diseases
Dexamethasone acetate
Hydrocortisone acetate
Hydrocortisone 17-butyrate 21-propionate
Cortisol succinate
Dexamethasone
Hydrocortisone
Dexamethasone 21-phosphate
BB 1101
Hydrocortisone-17-butyrate
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents

ClinicalTrials.gov processed this record on September 30, 2014