Mild Autonomous Cortisol Secretion (MACS), Autonomous Cortisol Secretion (ACS)
Conditions
Keywords
Hypercortisolism, Cortisol excess, Cushing Syndrome, Adrenal adenoma, Adrenal hyperplasia
Brief summary
single-center, randomized, double-blind, placebo-controlled Phase 2 study to evaluate safety and efficacy of overnight metyrapone in patients with MACS.
Detailed description
This study is a double blind, placebo-controlled phase II trial of the safety and efficacy of Metyrapone, in the treatment of MACS. Subjects will be remotely screened and interested qualified subjects will be remotely consented. Subjects will be randomized 2:1 for 6 months of the main study. At 6 months, two options will be available for subjects for months 6-12: open-label arm, observational arm.
Interventions
Subjects will receive metyrapone beginning at 500 mg and titrating up to 1000 mg
DRUGPlacebo
Subjects will receive placebo at 500 mg dose and titrated up to 1000 mg to match interventional arm and prevent unblinding
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provide written informed consent. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. Age ≥ 18 years 4. Diagnosed with MACS i. at least 2 abnormal post-dexamethasone cortisol results1 mg post-dexamethasone cortisol \>1.8 mcg/dL or ii. 8 mg post-dexamethasone cortisol \>1 mcg/dL b. Historical dexamethasone suppression test results can be used if performed within 24 months prior to enrollment. 5. Adrenal imaging phenotype consistent with benign disease (adrenal adenoma/s, macronodular or micronodular adrenal hyperplasia) 6. At least one of the following comorbidities: 1. obesity (BMI\>30 kg/m2) 2. dysglycemia 3. dyslipidemia 4. hypertension 5. osteopenia 6. osteoporosis 7. fragility fractures 7. Ability to take oral medication and be willing to adhere to the study intervention regimen. 8. For persons of childbearing potential: : agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of ≤ 5% per year during the treatment period and for 1 month after the last dose of study treatment. 9. Stable timing for bedtime for at least one week prior to on-site study visits. 10. History of difficulty providing blood via standard blood draw methods
Exclusion criteria
1. Planned alternative therapy for MACS within 12 months after joining the study. 2. Current use of oral exogenous glucocorticoid therapy 3. Current use of opioid therapy \>20 MME/day 4. Planned use of oral exogenous glucocorticoid therapy 5. Planned use of opioid therapy \>20 MME/day 6. Use of injectable glucocorticoid within 6 weeks prior to Day 1 7. Investigator's judgement based on history/physical examination that a comorbidity or concomitant medication may impact the hypothalamic-pituitary-adrenal axis or steroid metabolome 8. Uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness/social situations that would limit compliance with study requirements 9. Pregnancy or lactation 10. Known allergic reactions to metyrapone 11. Suspected false positive post-dexamethasone cortisol results due to increased metabolism, poor absorption, or noncompliance with dexamethasone 12. Treatment with another investigational drug or other intervention within lower than specific therapy washout period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucocorticoid to androgen ratio | 3 and 6 months | Glucocorticoid to androgen ratio will be calculated based on total glucocorticoids and total androgens measured through 25-steroid urine profiling. |
| Delta salivary cortisone | 3 and 6 months | Waking salivary cortisone and bedtime salivary cortisone will be assessed, and delta calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adrenal insufficiency symptoms as assessed by the AddiQoL Survey | Baseline, 1 week post dose titration, 3 and 6 months | The investigators will administer AddiQoL Survey at baseline, 1 week after each dose titration, and at 3 and 6 months. |
| Adrenal insufficiency as assessed through morning ACTH and cortisol measurements. | baseline, 3, 6 months | The investigators will measure ACTH and cortisol in the morning at baseline, 3 and 6 months to assess for biochemical adrenal insufficiency. |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 0-6 months | The investigators will assess adverse events using CTCAE v4.0 at baseline and continuously. |
| Improvement in hypertension | 3 and 6 months | The investigators will assess for improvement in hypertension using a composite assessment: 1) improvement in blood pressure measurements while on stable therapy, or 2) stable blood pressure measurements while on a lower intensity hypertension therapy. |
| Quality of life as assessed by SF36 form | 3 and 6 months | The investigators will assess quality of life using SF36 at baseline, 3 and 6 months. |
| Improvement in hyperglycemia | 3 and 6 months | The investigators will assess for improvement in hyperglycemia by using a composite assessment defined as: 1) decrease in fasting glucose of Hb1C, or 2) Stable biochemical measurements with a decrease in intensity of hyperglycemia therapy |
| Change in body mass index (BMI) | 3 and 6 months | The investigators will assess for change in the body mass index with metyrapone therapy. |
Contacts
Primary ContactVanessa Fell, MA
Outcome results
None listed