Blocking cortisol metabolism to improve mild Cushing's syndrome due to an adrenal nodule

INTERVENTION: 40 patients with Mild Autonomous Cortisol Secretion (MACS) will be recruited and undergo 2 days of baseline investigations. They will then be randomized using an online tool to receive the IMP (SPI‐62 6 mg once daily, n = 20) or placebo (n = 20) for 12 weeks. Follow‐up visits will occur 4, 8 and 12 weeks after treatment is started. All baseline investigations are repeated after 12 weeks of SPI‐62 or placebo treatment. CONDITION: Mild autonomous cortisol secretion due to an adrenal adenoma ; Nutritional, Metabolic, Endocrine PRIMARY OUTCOME: Glucose disposal as measured across the hyperinsulinaemic euglycaemic clamp using stable isotope glucose tracers at baseline and 12 weeks SECONDARY OUTCOME: 1. Serum markers of bone turnover including Procollagen type 1 N‐terminal pro‐peptide, type I collagen cross‐linked N‐telopeptide and osteocalcin measured using ELISAs at 4, 8 and 11 weeks; 2. Cognitive function assessed using the CogState battery of tests at baseline and 11 weeks; 3. 24‐hour ambulatory blood pressure measurements using an ambulatory blood pressure monitor at baseline and 11 weeks; 4. Endogenous glucose production rate during a hyperinsulinaemic euglycaemic clamp measured using stable isotope glucose tracers at baseline and 11 weeks; 5. Total and regional lean and fat mass on DXA scan and intra‐abdominal fat mass on single slice CT image at baseline and 11 weeks; 6. Steroid metabolites measured by gas chromatography, mass spectrometry in a timed overnight urine sample at 4, 8 and 11 weeks; 7. Circulating inflammatory cytokines, isolation of peripheral blood mononuclear cells and defining their response to inflammatory stress measured using cell proliferation assays and ELISAs at baseline and 11 weeks; 8. Continuous glucose monitoring using interstitial glucose sensors at baseline, 4‐6 and 8‐10 weeks; 9. Gene expression changes measured in adipose tissue biopsies using PCR gene expression analysis at baseline and 11 weeks; 10. Safety and tolerability measured using clinical data and serum biochemical assessments at baseline and 11 weeks INCLUSION CRITERIA: 1. Participant is willing and able to give informed consent for participation in the trial 2. Aged 18 years or above 3. 09.00 h serum cortisol >51 nmol/L after overnight dexamethasone (1 mg) within the last 6 months performed in the absence (for at least 4 weeks prior to testing) of concomitant estrogen‐containing medication. 4. Adrenal adenoma(s) that has (have) not been surgically removed, and with benign characteristics on cross‐sectional imaging. 5. Body mass inde X18 to 45 kg/m2 6. Stable dose of current regular antihypertensive and/or glucose‐lowering medication for at least 12 weeks prior to trial entry. 7. Female participants of childbearing potential and male participants whose partner is of childbearing potential must be willing to ensure that they and their partner use effective contraception during the trial and for 90 days thereafter. 8. In the Investigator’s opinion, the participant is able and willing to comply with all trial re