Metyrapone for Mild Autonomous Cortisol Secretion

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Glucocorticoids, Opioids

Disqualifiers: Pregnancy, Active infection, Cardiac arrhythmia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safety and effectiveness of metyrapone for treating Mild Autonomous Cortisol Secretion (MACS), a condition where the body produces excess cortisol without a stress trigger. Participants will take metyrapone for six months, with an option to extend the treatment for an additional 30 months. Suitable candidates have MACS and may also experience health issues such as obesity, high blood pressure, or bone problems like osteopenia. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant medical advancements.

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.

Is there any evidence suggesting that metyrapone is likely to be safe for humans?

Research has shown that metyrapone is usually well-tolerated by people with Mild Autonomous Cortisol Secretion (MACS). In one study, 12 out of 15 patients continued using metyrapone without major issues. However, some side effects occurred: two people stopped taking it due to diarrhea, and one woman experienced increased levels of certain hormones. No other serious problems were reported.

Another study found that metyrapone is a safe treatment option, helping to manage conditions like high blood pressure in patients with MACS. Overall, research suggests that metyrapone is a safe choice for many, but like any treatment, it can have side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for Mild Autonomous Cortisol Secretion (MACS) focus on reducing cortisol production through various medications like ketoconazole or mitotane. But metyrapone works differently, directly targeting the enzyme that produces cortisol, potentially offering a more direct approach to managing cortisol levels. Researchers are excited about metyrapone because it offers a new mechanism of action, which could lead to more effective management of cortisol levels with potentially fewer side effects. This could be a game-changer for patients looking for an alternative to the current standard treatments.

What evidence suggests that metyrapone might be an effective treatment for Mild Autonomous Cortisol Secretion?

Research has shown that metyrapone, the treatment under study in this trial, can help manage mild autonomous cortisol secretion (MACS). In earlier studies, patients taking metyrapone experienced noticeable improvements in blood pressure, with levels reaching 120/70 after just two weeks. This suggests that metyrapone effectively controls excess cortisol, often linked to high blood pressure. However, surveys measuring patient quality of life did not show significant changes over time, indicating that the effect on overall well-being may vary. While these findings are promising, more research is needed to fully understand metyrapone's effects on MACS. ^{1 3 5 6 7}

Who Is on the Research Team?

Irina Bancos, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Metyrapone

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.

How Is the Trial Designed?

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.

Metyrapone is already approved in United States, European Union for the following indications:

Approved in United States as Metopirone for:

• Diagnosis of adrenal insufficiency
• Treatment of Cushing’s syndrome

Approved in European Union as Metopirone for:

• Diagnosis of adrenal insufficiency
• Treatment of Cushing’s syndrome

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Published Research Related to This Trial

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]

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, 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 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]

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]

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]

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 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]

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]

Citations

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Metyrapone for Mild Autonomous Cortisol Secretion (MACS)

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 ...

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AddiQol survey scores did not change significantly between baseline, 3 and 6 months. Conclusion: Metyrapone therapy in patients with MACS ...

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Metyrapone for Mild Autonomous Cortisol Secretion

The purpose of this study is to evaluate the safety and tolerability of metyrapone therapy in patients with mild autonomous cortisol secretion (MACS).

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NCT07138274 | Metyrapone Study for Patients Diagnosed ...

This study is a double blind, placebo-controlled phase II trial of the safety and efficacy of Metyrapone, in the treatment of MACS. Subjects ...

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Metyrapone treatment for mild autonomous cortisol ...

Upon approval by the hospital pharmacy, metyrapone was started at a night dose of 250 mg. After 2 weeks, BP improved notably, reaching 120/70 ...

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6927 Metyrapone To Reset The Nocturnal Cortisol Rhythm In ...

Results: Metyrapone was tolerated by 12/15 patients - two stopped due to diarrhea and one due to high androgens in a female. There were no ...

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SUN-448 Overnight Metyrapone Therapy in Patients with ...

Objectives: To evaluate the tolerability and safety of overnight metyrapone in adults with MACS. Methods: Study design: Open-Label, Phase 2, ...