TY - JOUR
T1 - Randomized Trial of Osilodrostat for the Treatment of Cushing Disease
AU - Gadelha, Mônica
AU - Bex, Marie
AU - Feelders, Richard A.
AU - Heaney, Anthony P.
AU - Auchus, Richard J.
AU - Gilis-Januszewska, Aleksandra
AU - Witek, Przemyslaw
AU - Belaya, Zhanna
AU - Yu, Yerong
AU - Liao, Zhihong
AU - Ku, Chih Hao Chen
AU - Carvalho, Davide
AU - Roughton, Michael
AU - Wojna, Judi
AU - Pedroncelli, Alberto M.
AU - Snyder, Peter J.
N1 - Publisher Copyright:
© 2022 The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Context: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. Methods: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC≤ULN at week 12. The key secondary endpoint was the proportion achieving mUFC≤ULN at week 36 (after 24 weeks' open-label osilodrostat). Results: Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1×ULN/2.5×ULN) received randomized treatment with osilodrostat (n=48) or placebo (n=25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC≤ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P<0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC≤ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). Conclusion: Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.
AB - Context: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. Methods: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC≤ULN at week 12. The key secondary endpoint was the proportion achieving mUFC≤ULN at week 36 (after 24 weeks' open-label osilodrostat). Results: Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1×ULN/2.5×ULN) received randomized treatment with osilodrostat (n=48) or placebo (n=25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC≤ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P<0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC≤ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). Conclusion: Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.
UR - http://www.scopus.com/inward/record.url?scp=85132451639&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgac178
DO - 10.1210/clinem/dgac178
M3 - Article
C2 - 35325149
AN - SCOPUS:85132451639
VL - 107
SP - E2882-E2895
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 7
ER -
