A Phase 2 interventional study of AZD4017 and prednisolone and Placebo Oral Tablet and prednisolone in Iatrogenic Cushing's Disease, sponsored by University of Oxford. Completed at 1 site in United Kingdom. Open to male participants aged 18 Years to 60 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-05-13.
Sponsored by University of Oxford · Phase 2, Interventional, and Treatment
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:
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.
The following criteria apply to both arms and each volunteer who has a successful screening visit will be randomized to one of the arms defined above (see section 6): We estimate that we will need to screen 40-50 patients in order to achieve our recruitment target.
For male study subjects whose partner is pregnant, or whose partner is a woman of child-bearing potential (WOCBP) who is established on and continuing to use a highly effective method of contraception, in addition to the stipulations above, males should continue to use a condom (in addition to the highly effective method) for 1 week following the last dose of study drug (5 drug elimination half-lives rounded up to 1 week).
For male study subjects whose partner is not pregnant but is a WOCBP who is not established on and continuing to use a highly effective method of contraception, males should continue to use a condom (in addition to the highly effective method) for 3 weeks following the last dose of study drug (5 drug elimination half-lives plus 2 weeks).
Male study participants must also not donate sperm from the time of screening until 3 weeks after final dose of study drug (5 drug elimination half-lives plus 2 weeks).
Highly effective methods of contraception are defined as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (either oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (either oral [specifically Cerazette™], injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence.
We would advise that competitive elite athletes do not take part in the study as there is the possibility that the prednisolone could impact upon their athletic performance
Exclusion Criteria:
The participant may not enter the study if any of the following apply:
Prednisolone 20mg once daily and AZD4017 400mg twice daily for 7 days.
Drug: AZD4017 and prednisolone
Prednisolone 20mg once daily and placebo twice daily for 7 days.
Drug: Placebo Oral Tablet 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.
Also known as: 11 beta-Hydroxysteroid dehydrogenase inhibitor
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.
Also known as: Placebo
Changes in the detrimental side effects of prednisolone by AZD4017.
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.
Time frame: 2 years
Changes in hepatic insulin sensitivity by AZD4017 when given with prednisolone (20mg) compared to prednisolone (20mg) given alone.
Measurement of endogenous glucose production rate during a hyperinsulinaemic euglycaemic clamp.
Time frame: 2 years
Changes in blood pressure associated with prednisolone and AZD4017 administration
The participants will have 24h ambulatory blood pressure measurements taken.
Time frame: 2 years
Changes in adipose tissue gene expression profile associated with prednisolone and AZD4017 administration.
Gene expression changes will be measured from adipose tissue biopsies.
Time frame: 2 years
Change in whole body oxidation associated with prednisolone and AZD4017 administration
Measurement of incorporation of carbon-13 into breath carbon dioxide using Gas chromatography combustion isotope ratio mass spectrometry.
Time frame: 2 years
Changes in skeletal muscle gene expression profile associated with prednisolone and AZD4017 administration.
Gene expression changes measured in skeletal muscle biopsies.
Time frame: 2 years
Changes in circulating inflammatory cytokines and inflammatory response in circulating inflammatory cells associated with prednisolone and AZD4017 administration.
Measurement of inflammatory cytokines, isolation of peripheral blood mononuclear cells and defining their response to inflammatory stress.
Time frame: 2 years
Changes in bone turnover associated with prednisolone and AZD4017 administration.
Measurement of serum and urine markers of bone turnover including type I collagen cross-linked N-telopeptide and osteocalcin
Time frame: 2 years
Changes in body composition (total and regional lean and fat mass) associated with prednisolone and AZD4017 administration.
Measurement of total and regional lean and fat mass on dual energy x-ray absorptiometry scan.
Time frame: 2 years
Changes in urinary steroid metabolite profile associated with prednisolone and AZD4017 administration.
Steroid metabolites measured by gas chromatography, mass spectrometry in a timed overnight urine sample.
Time frame: 2 years
Plan to share: No
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