Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition
Condition: Iatrogenic Cushing's Disease
MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Cushing Syndrome
Study type: Interventional
Phase: Phase 2

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 demonstrate the beneficial effect of the selective 11β-HSD1 inhibitor, AZD4017, upon
           the prednisolone-induced deterioration in metabolic phenotype, including glucose
           disposal and endogenous glucose production rates.

        2. To determine the impact of AZD4017 on the anti-inflammatory actions of Prednisolone.

        3. To identify the tissue-specific (skeletal muscle, adipose) mechanisms underpinning the
           response to Prednisolone therapy administered in conjunction with AZD4017.

      The investigators will perform a randomized, double-blind placebo controlled study to
      determine if co-administration of the selective 11β-HSD1 inhibitor, AZD4017, limits the
      adverse effects of short-course exogenous glucocorticoid administration. 32 healthy male
      volunteers will have detailed metabolic investigations including 2-step hyperinsulinaemic
      euglycaemic clamps (with stable isotope measurements of lipid and carbohydrate metabolism),
      as well as assessment of skeletal muscle forearm glucose uptake. All volunteers will then be
      treated with Prednisolone (20mg daily) and randomized to the co-administration of placebo or
      AZD4017. After 1 week of therapy, all investigations will be repeated. Our hypothesis is that
      the adverse metabolic effects of Prednisolone will be reduced by co-administration of
      AZD4017.
    


Intervention name(s): AZD4017 and prednisolone; Placebo Oral Tablet and prednisolone
Intervention type(s): Drug; Drug
Intervention description(s): The drug AZD4017 will be given together with prednisolone 20mg daily for 7 days to compare its effects on metabolic tissues against the placebo arm where the participants will take placebo and prednisolone 20mg daily for 7 days.; Placebo Oral tablet will be given together with prednisolone 20mg daily for 7 days to compare the effects on metabolic tissues of AZD4017 and prednisolone 20mg daily against the placebo arm.
Other intervention name(s): 11 beta-Hydroxysteroid dehydrogenase inhibitor; Placebo
Intervention MeSH terms: Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Corticosteroids; Prednisolone; 11 beta-Hydroxysteroid dehydrogenase1 inhibitor; Iatrogenic Cushing's disease; AZD4017