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

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 three 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 24h 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% confidence interval [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%); eight 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.