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Clinical Trial
. 2025 Aug 29;193(3):391-402.
doi: 10.1093/ejendo/lvaf181.

Prospective study of metyrapone in endogenous Cushing's syndrome (PROMPT)

Lynnette K Nieman  1 , Marco Boscaro  2 , Carla Scaroni  2 , Timo Deutschbein  3   4 , Emese Mezôsi  5 , Natacha Driessens  6 , Carmen E Georgescu  7 , Marcin Motyka  8 , Alicja Hubalewska-Dydejczyk  9 , Barbara Jarzab  10 , Dominique Maiter  11 , Martin Reincke  12 , Paola Loli  13 , Benedetta Zampetti  14 , Aysegul Atmaca  15 , Corin Badiu  16 , Albert Beckers  17 , Marek Bolanowski  18 , Francesco Cavagnini  19 , Nicole Unger  20 , Roberta Giordano  21 , Felicia Alexandra Hanzu  22 , Massimo Terzolo  23 , Myriam Bou Nader  24 , Ninet Sinaii  25 , Judit Tőke  26 , Miklós Tóth  26
Affiliations
Clinical Trial

Prospective study of metyrapone in endogenous Cushing's syndrome (PROMPT)

Lynnette K Nieman et al. Eur J Endocrinol. .

Abstract

Objective: We evaluated the safety and efficacy of metyrapone treatment for Cushing's syndrome (CS).

Design: International, prospective, single-arm, open-label study.

Methods: Fifty adults with endogenous CS (either unsuitable for or uncontrolled after surgery) and 3 urinary free cortisol (UFC) concentrations each ≥1.5-fold the upper limit of normal (ULN) were enrolled. After 12 weeks of metyrapone titration, participants with mean 24 h UFC (mUFC) ≤ 2-fold ULN could enter a 24-week extension phase. Safety was assessed, and doses adjusted at weeks 1-5, 8, 12, and 24. Pre-defined endpoints included normalization of mUFC at weeks 12 (primary), 24, and 36, and proportion of "responders" (normalization or ≥50% decrease of baseline mUFC), time to eucortisolemia, salivary cortisol day-curve, and quality of life (QoL).

Results: Of the 49 evaluable participants, 47 completed the 12-week visit; 40 were evaluated at week 24 and 35 at week 36. The primary endpoint was met in 46.9% of participants (95% CI 32.5%-61.7%), with efficacy maintained at week 24 (52.5%; 95% CI 37.5%-67.1%) and week 36 (48.6%; 95% CI 33.0%-64.4%). The responder rates were 80.9%, 77.5%, and 71.4% at weeks 12, 24, and 36, respectively. Forty-seven participants (94%) developed mild-to-moderate adverse events (AEs), mostly during the first 12 weeks and most commonly nausea (38%), fatigue (26%), and headache (22%); 8 experienced severe AEs. Six participants developed reversible adrenal insufficiency during titration. Clinical features and QoL improved.

Conclusion: Metyrapone is a safe and effective treatment for endogenous CS.

Keywords: Cushing's syndrome; late-night salivary cortisol; metyrapone; urinary free cortisol.

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Conflict of interest statement

Conflict of interest: L.K.N. has been an author and editor of UpToDate. T.D. has received travel costs from Recordati Rare Diseases; lecture fees from Recordati Rare Diseases; honoraria for scientific board activities from HRA Pharma; and has served as a principal investigator and national study coordinator for clinical studies for Corcept Therapeutics. A.H.-D. has received speaker honoraria from IBSEN, Merck, Berlin, Chemie/Menarini, and Recordati. B.J. has received honoraria from Amgen, AstraZeneca, Bayer Health Care, Eisai, Ewopharma, Exelixis, Ipsen, Oxygene, Lilly, Pfizer, Sanofi-Genzyme, and Sobi. M.R. has been a consultant for Recordati Rare Diseases, Lundbeck, HRA Pharma/Esteve, and Crinetics; and has received speaking fees from HRA Pharma/Esteve and Recordati. F.A.H. has been a speaker and consultant for Esteve. Ma.T. has been a consultant for Corcept Therapeutics, Recordati Rare Diseases, and Esteve; and has received speaking fees from Esteve. M.B.N. has acted as a consultant for HRA Pharma Rare Diseases. Mi.T. has been a speaker and occasional consultant for Medis and Recordati. Marc.B., C.S., E.M., N.D., C.E.G., M.M., D.M., P.L., B.Z., A.A., C.B., A.B., Mare.B., F.C., N.U., R.G., N.S., and J.T. have no conflicts of interest to declare. HRA Pharma, the sponsor and funder, contributed to the study design, the analysis and interpretation of the data, and the writing of this report. Data were available to all authors. The corresponding author wrote the initial protocol, analyzed the data, and wrote the report; the National Institute of Health and HRA Pharma statisticians performed the statistical analysis. All other authors were responsible for patient accrual and protocol procedures. All authors revised the manuscript and agreed to submit the report for publication.

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