Efficacy of Metyrapone in Patients with Primary Bilateral Macronodular Adrenal Hyperplasia and Mild Autonomous Cortisol Secretion: A Randomized Controlled Trial

The primary objective is to demonstrate that the inhibition of cortisol secretion via the steroidogenesis inhibitor metyrapone leads to the improvement of hypertension and diabetes in patients with Primary Bilateral Macronodular Adrenal Hyperplasia presenting with mild autonomous cortisol secretion. 3, 5

Secondary objectives include:

• Determination of the steroid profile response, ACTH levels, and the degree of steroid inhibition.
• Evaluation of the effects of metyrapone on body mass index, insulin sensitivity, and the lipid profile.
• Quantitative assessment of changes in blood pressure via 24h ambulatory blood pressure monitoring and HbA1c levels.
• Analysis of the impact on quality of life and depression.
• Investigation of genetic factors associated with clinical and hormonal responses.
• Assessment of safety regarding the occurrence of adrenal insufficiency. 4

The sponsor did not provide information regarding the total number of participants. The study population consists of both male and female patients. The age range is categorized under codes 3 and 4. Participants are diagnosed with primary bilateral macronodular adrenal hyperplasia causing moderate Cushing syndrome characterized by mild autonomous cortisol secretion. Inclusion requires adrenal imaging via computed tomography or magnetic resonance imaging demonstrating multiple bilateral supracentrimetric nodules. Clinical requirements include a plasma cortisol level after a 1 mg overnight dexamethasone test exceeding 50 nmol/L and urinary free cortisol below 1.5 times the upper limit of normal. Adrenal origin must be confirmed by morning plasma ACTH levels below 10 pg/ml or between 10 and 20 pg/ml without response to corticotropin-releasing hormone stimulation. Eligible subjects must present with hypertension or diabetes. Women of childbearing potential must have a negative human chorionic gonadotropin test and utilize highly effective contraception, while men must utilize an effective method of contraception. All participants must be French speaking and have provided written informed consent.

This randomized trial is designed to evaluate the benefit of metyrapone in patients diagnosed with primary bilateral macronodular adrenal hyperplasia presenting with mild autonomous cortisol secretion. The study methodology involves a comparison between the test product and a placebo to assess the inhibition of cortisol secretion and its impact on comorbid conditions. The primary objective is to demonstrate improvement in hypertension and diabetes. The clinical assessment includes a screening process to confirm eligibility based on adrenal imaging, plasma cortisol levels, and ACTH levels. Following inclusion, participants undergo a treatment period with evaluations at baseline, 3 months, and 6 months. The primary endpoint is measured at 6 months of treatment and focuses on the number of patients achieving improved blood pressure control and/or improved glycemic status. Secondary endpoints include changes in urinary cortisol, salivary cortisol, steroid profiles, insulin sensitivity, and various quality of life metrics. The total duration of participant involvement is estimated to be 6 months of treatment following the initial screening.

The experimental treatment consists of metyrapone administered in the form of a 250 mg soft capsule. The total daily dose is 2000 mg, which is delivered via the oral route.

The control group receives a placebo formulated to match the appearance of the 250 mg metyrapone soft capsule.

The primary efficacy endpoint is the number of patients achieving improvement of blood pressure control and/or improvement of diabetes at 6 months of treatment. This assessment is conducted in patients with Primary Bilateral Macronodular Adrenal Hyperplasia presenting with mild autonomous cortisol secretion.

Secondary efficacy assessments include the evaluation of urinary cortisol, salivary cortisol during the circadian rhythm, steroid profile via mass spectrometry analysis, and morning ACTH plasma level at M0, M3, and M6. Metabolic parameters, including Body Mass Index, insulin sensitivity as determined by HOMA, glycemia via continuous glucose monitoring, total cholesterol, HDL, LDL, and triglyceride levels, are also measured at M0, M3, and M6. Additional clinical measures consist of the mean change from baseline to M6 in day-time and night-time systolic and diastolic blood pressure and the mean change in HbA1c.

The assessment of quality of life and depression includes the use of the Medical Outcomes Study 36-item short-form health survey (SF-36), the Beck Depression Inventory (BDI-II), and the QolCushing questionnaire at M0, M3, and M6. Furthermore, the clinical and hormonal response will be compared according to ARMC5, PDE11A4, and NR3C1 genotypes.