Clinical Trial: An Investigational Study of Hydrocortisone

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: 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 Adul

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 Summary: 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.
Sponsor: Diurnal Limited

Current Primary Outcome:

  • Maximum Serum Concentration (Cmax) [ Time Frame: Hourly from 0 to 24 hours ]
    Derived PK for Serum Cortisol: Maximum serum concentration (Cmax)
  • AUC0-t [ Time Frame: Hourly from 0 to 24 hours ]
    Derived PK for Serum Cortisol: Area under the curve from 0-24 hours


Original Primary Outcome:

  • 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 ]

    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 ]
    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 subjec

    Current Secondary Outcome:

    • Adverse Events (AEs) [ Time Frame: Days 1-2 during each Study Period ]
      Number of subjects with adverse events throughout the study.
    • Concentrations of Cortisol Binding Protein [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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.


    Original Secondary Outcome:

    • To assess the safety and tolerability of Infacort Granules and hydrocortisone throughout the study. [ Time Frame: Days 1-2 during each Study Period ]
      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 ]

      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 ]
      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 ]

      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 ]
      Exploratory Investigation: Plasma metabolome


    Information By: Diurnal Limited

    Dates:
    Date Received: October 6, 2013
    Date Started: October 2013
    Date Completion:
    Last Updated: April 12, 2017
    Last Verified: April 2017