Clinical Trial: Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition (TICSI)

Brief Summary:

Currently, 2-3% of the population of the United Kingdom and United States of America receive glucocorticoid therapy. Significant adverse effects are not confined to chronic use; recurrent short-course administration is associated with increased morbidity and mortality. The adverse metabolic features associated with glucocorticoid use include obesity, skeletal muscle myopathy, hypertension, insulin resistance and diabetes and are collectively termed 'iatrogenic Cushing's syndrome'. The efficacy of glucocorticoid therapy is not in doubt, but there are no interventions to reduce their metabolic consequences. Within metabolic tissues (liver, skeletal muscle, adipose), 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid and therefore is able to tightly control the availability of glucocorticoids to activate the glucocorticoid receptor. In preclinical studies, the investigators have shown that 11β-HSD1 is critical in regulating the development of the adverse features associated with circulating glucocorticoid excess, endorsing our observations in a patient with Cushing's disease, who was protected from a classical phenotype due to a functional deficit in 11β-HSD1.

This study is the first clinical evaluation of the impact of the selective 11β-HSD1 inhibitor, AZD4017, in healthy volunteers taking exogenous glucocorticoids (prednisolone). The investigators propose that in tissues expressing high levels of 11β-HSD1, prednisolone action will be amplified, driving adverse effects within these tissues and have hypothesized that AZD4017 in humans will reduce the adverse metabolic consequences of Prednisolone administration without compromise to its anti-inflammatory action.

Our specific research objectives are:

  1. To evaluate whether AZD4017 can limit the detrimental effect of prednisolone (20mg) on glucose disposal. This will be achieved by measuring glucose disposal during a hyperinsulinaemic euglycaemic clamp.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Changes in hepatic insulin sensitivity by AZD4017 when given with prednisolone (20mg) compared to prednisolone (20mg) given alone. [ Time Frame: 2 years ]
    Measurement of endogenous glucose production rate during a hyperinsulinaemic euglycaemic clamp.
  • Changes in blood pressure associated with prednisolone and AZD4017 administration [ Time Frame: 2 years ]
    The participants will have 24h ambulatory blood pressure measurements taken.
  • Changes in adipose tissue gene expression profile associated with prednisolone and AZD4017 administration. [ Time Frame: 2 years ]
    Gene expression changes will be measured from adipose tissue biopsies.
  • Change in whole body oxidation associated with prednisolone and AZD4017 administration [ Time Frame: 2 years ]
    Measurement of incorporation of carbon-13 into breath carbon dioxide using Gas chromatography combustion isotope ratio mass spectrometry.
  • Changes in skeletal muscle gene expression profile associated with prednisolone and AZD4017 administration. [ Time Frame: 2 years ]
    Gene expression changes measured in skeletal muscle biopsies.
  • Changes in circulating inflammatory cytokines and inflammatory response in circulating inflammatory cells associated with prednisolone and AZD4017 administration. [ Time Frame: 2 years ]
    Measurement of inflammatory cytokines, isolation of peripheral blood mononuclear cells and defining their response to inflammatory stress.
  • Changes in bone turnover associated with prednisolone and AZD4017 administration. [ Time Frame: 2 years ]
    Measurement of serum and urine markers of bone turnover including type I collagen cross-linked N-telopeptide and osteocalcin
  • Changes in body composition (total and regional lean and fat mass) associated with prednisolone and AZD4017 administration. [ Time Frame: 2 years ]
    Measurement of total and regional lean and fat mass on dual energy x-ray absorptiometry scan.
  • Changes in urinary steroid metabolite profile associated with prednisolone and AZD4017 administration. [ Time Frame: 2 years ]
    Steroid metabolites measured by gas chromatography, mass spectrometry in a timed overnight urine sample.


Original Secondary Outcome: Same as current

Information By: University of Oxford

Dates:
Date Received: March 17, 2017
Date Started: May 2017
Date Completion: January 2019
Last Updated: April 24, 2017
Last Verified: April 2017