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

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.

Conditions

• Iatrogenic Cushing's Disease

Interventions

DRUG

AZD4017 and prednisolone

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.

DRUG

Placebo Oral Tablet and prednisolone

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.

Sponsors & Collaborators

• AstraZeneca

  collaborator INDUSTRY

• University of Oxford

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

60 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2017-05-25

Primary Completion

2020-08-01

Completion

2020-08-01

Countries

• United Kingdom

Study Locations