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

Inclusion Criteria

• •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.
• •Male volunteers without diabetes (HbA1C \< 48mmol/mol at screening)
• •BMI 20-30kg/m2
• •Age 18-60years
• •For individuals identified from Oxford Biobank - fasting insulin and / or glucose and / or insulin resistance as measured by Homeostatic model assessment (HOMA) - insulin resistance in the 40th-60th percentile
• •BP\<160/100 mmHg with stable antihypertensive therapy for \>3 months
• •Stable lipid lowering therapy for \>3 months
• •No contraindications to AZD4017 or prednisolone treatment Study participants who are sexually active with a female partner of childbearing potential must be surgically sterilized, practicing true abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence, e.g. calendar, ovulation, symptothermal, post-ovulation methods, declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception) or agree, along with their partners, to use two forms of highly effective methods of birth control (i.e. condom plus another highly effective method defined below), and not rely on barrier methods and spermicide alone, from the time of screening and for the duration of the study. For the proposed clinical study, all study subjects will be male.
• •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