Metyrapone for Mild Autonomous Cortisol Secretion

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Mayo Clinic

Must not be taking: Glucocorticoids, Opioids

Disqualifiers: Pregnancy, Active infection, Cardiac arrhythmia, others

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether the study drug, metyrapone, is safe and effective in treating participants with Mild Autonomous Cortisol Secretion (MACS).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot use oral glucocorticoids or opioids over 20 MME/day. If you are on these, you may need to stop or adjust them before joining the study.

What data supports the effectiveness of the drug metyrapone for treating mild autonomous cortisol secretion?

Metyrapone has been shown to reduce cortisol levels in patients with Cushing's syndrome, a condition characterized by excess cortisol. In one study, metyrapone alone reduced cortisol levels in patients, and when combined with another drug, it further decreased cortisol levels. This suggests that metyrapone can effectively lower cortisol, which may be beneficial for conditions involving excess cortisol secretion. ^{1 2 3 4 5}

Is metyrapone generally safe for humans?

Metyrapone has been studied in various contexts and is generally well tolerated in humans, as shown in a study where it did not worsen the effects of cocaine in users. However, it can affect emotions and memory at higher doses, and its combination with other drugs like sodium valproate has been explored for treating conditions like Cushing's syndrome. ^{1 2 6 7 8}

How does the drug metyrapone differ from other treatments for mild autonomous cortisol secretion?

Metyrapone is unique because it works by inhibiting the enzyme 11β-hydroxylase, which reduces cortisol production, a mechanism not commonly used in other treatments for mild autonomous cortisol secretion. This approach is particularly useful in conditions like Cushing's syndrome, where controlling cortisol levels is crucial. ^{1 2 3 9 10}

Research Team

Irina Bancos, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for adults with Mild Autonomous Cortisol Secretion (MACS), evidenced by specific cortisol test results. Participants must have certain conditions like obesity or hypertension, be able to take oral meds, and commit to the study's duration. Women of childbearing age should use effective contraception.

Inclusion Criteria

You have given written consent.

I can take pills and will follow the study's treatment plan.

I have at least one of the following: obesity, blood sugar issues, abnormal cholesterol levels, high blood pressure, weak bones, or fractures from fragility.

Exclusion Criteria

Known allergic reactions to metyrapone

I have used injectable steroids in the last 6 weeks.

I might have had a false positive cortisol test after taking dexamethasone.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Open Label Phase

Participants receive metyrapone for a 6 month treatment period

6 months

Optional Extension Phase

Participants may opt to continue metyrapone therapy for an additional 30 months

30 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

Treatment Details

Interventions

• Metyrapone (Corticosteroid)

Trial Overview The trial is testing metyrapone's safety and effectiveness in treating MACS. It involves taking this oral medication and adhering to a treatment regimen while researchers monitor its impact on participants' health over time.

Participant Groups

Group I: Mild Autonomous Cortisol Secretion (MACS) Open Label Phase and Optional Extension Phase Experimental Treatment 1 Intervention

Subjects diagnosed with Mild Autonomous Cortisol Secretion (MACS) will receive metyrapone for a 6 month treatment period (Open Label Phase) with the option to continue for an additional 30 months of metyrapone therapy. If a patient chooses to participate in the Optional Extension Phase they will continue to receive metyrapone therapy until Month 36. This is an additional 30 months of therapy after completion of the Open Label Phase.

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

In a study involving six patients with Cushing's disease, the combination of metyrapone and sodium valproate led to a greater reduction in urinary free cortisol and plasma cortisol levels compared to metyrapone alone, indicating enhanced efficacy in managing the disease.

The addition of sodium valproate not only further decreased cortisol levels but also increased plasma 11-deoxycortisol, suggesting that valproate may act on both the hypothalamus and peripheral systems, potentially offering a new therapeutic approach for Cushing's syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combined use of sodium valproate and metyrapone in the treatment of Cushing's syndrome. Nussey, SS., Price, P., Jenkins, JS., et al.[2019]

In a study involving rats, the inhibition of corticosterone synthesis using metyrapone significantly reduced immobility time during a forced swim test, indicating an antidepressant-like effect.

The reduction in immobility was dose-dependently reversed by administering corticosterone, suggesting that elevated levels of this hormone can counteract the benefits of metyrapone, highlighting the role of stress hormones in depression-related behaviors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corticosterone influences forced swim-induced immobility. Báez, M., Volosin, M.[2019]

Oral metyrapone administration leads to a significant increase in ACTH levels within 60 minutes, indicating its effectiveness in assessing pituitary function in patients with adrenal insufficiency.

ACTH levels measured at 60 and 120 minutes can help predict whether patients will require glucocorticoid substitution, suggesting a potential for developing a streamlined ACTH-based testing protocol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dynamics of Adrenocorticotropin after Application of Metyrapone. Noe, S., von Werder, A., Iakoubov, R., et al.[2017]

Metyrapone, typically discouraged for long-term use in Cushing's syndrome due to potential adverse effects, was successfully used for nearly 6 years in a patient with refractory Cushing's syndrome with minimal side effects.

This case suggests that metyrapone may be a viable long-term treatment option for patients who do not respond to surgical resection, despite its usual limitations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metyrapone for Long-Term Medical Management of Cushing's Syndrome. Traina, AN., Farr, A., Malik, R., et al.[2021]

Metyrapone effectively reduced serum cortisol levels in 91 patients with various types of Cushing's syndrome, achieving target cortisol levels of less than 400 nmol/l in 75% of patients with pituitary-dependent Cushing's disease during short-term therapy.

The medication was well tolerated overall, with only rare side effects like transient hypoadrenalism and hirsutism, making it a valuable option for managing cortisol levels in Cushing's syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome. Verhelst, JA., Trainer, PJ., Howlett, TA., et al.[2022]

Metyrapone, an 11-beta-hydroxylase inhibitor, can suppress corticosterone levels in a dose-dependent manner, affecting emotional and cognitive functions; higher doses (50 mg/kg) impaired memory acquisition in a water maze task, while both doses impaired retention.

Different doses of metyrapone also produced varying effects on emotional responses: the higher dose reduced fear-induced immobility during stress, while the lower dose alleviated anxiety in a novel environment, suggesting that the drug's impact on learning and emotion is mediated through different adrenal steroid receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory. Roozendaal, B., Bohus, B., McGaugh, JL.[2019]

In a study involving 12 cocaine-dependent individuals, metyrapone was found to be well tolerated and did not worsen the physiological effects of cocaine, indicating its safety for potential outpatient use.

Metyrapone did not significantly change the subjective effects of cocaine, suggesting that while it may help in reducing stress-induced relapse, it does not interfere with the immediate drug experience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metyrapone and cocaine: a double-blind, placebo-controlled drug interaction study. Winhusen, T., Somoza, E., Harrer, JM., et al.[2013]

Metyrapone administration (400 mg/m2 every 4 hours for 5 to 9 days) effectively suppressed plasma and urinary aldosterone levels in most patients, indicating its potential as a treatment for conditions related to hyperaldosteronism.

Despite the suppression of aldosterone, there was no significant change in blood pressure across all patients, suggesting that metyrapone may not impact blood pressure regulation in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mineralocorticoid and metabolic response to metyrapone on normotensive children and children with dexamethasone-suppressible and primary hyperaldosteronism. Sonino, N., Levine, LS., New, MI.[2019]

In a study of 31 patients with Cushing's syndrome treated with metyrapone for at least 1 month, 70% achieved normalization of urinary-free cortisol (UFC) levels, indicating its effectiveness as a medical treatment.

Metyrapone was found to be safe, with no severe side effects reported, although some patients experienced hirsutism; the treatment led to a significant reduction in UFC and late-night salivary cortisol levels within the first month.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metyrapone treatment in Cushing's syndrome: a real-life study. Ceccato, F., Zilio, M., Barbot, M., et al.[2019]

Etomidate, a narcotic agent, did not affect plasma corticosterone levels or growth rates in female rats, indicating it may not be effective for altering growth through adrenal steroid inhibition.

Metyrapone showed complex effects: at moderate doses, it increased plasma DOC and corticosterone, while higher doses reduced corticosterone but caused toxicity and reduced growth in younger rats, highlighting the risks of using high doses for growth enhancement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of metyrapone and etomidate on adrenal function and growth rate in female rats. Sillence, MN., Rodway, RG.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

The combined use of sodium valproate and metyrapone in the treatment of Cushing's syndrome. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Corticosterone influences forced swim-induced immobility. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Dynamics of Adrenocorticotropin after Application of Metyrapone. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

Metyrapone for Long-Term Medical Management of Cushing's Syndrome. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Metyrapone and cocaine: a double-blind, placebo-controlled drug interaction study. [2013]

8. Denmark pubmed.ncbi.nlm.nih.gov

Mineralocorticoid and metabolic response to metyrapone on normotensive children and children with dexamethasone-suppressible and primary hyperaldosteronism. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Metyrapone treatment in Cushing's syndrome: a real-life study. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Effects of metyrapone and etomidate on adrenal function and growth rate in female rats. [2019]