Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)

Rosario Pivonello; Sabina Zacharieva; Atanaska Elenkova; Miklós Tóth; Ilan Shimon; Antonio Stigliano; Corin Badiu; Thierry Brue; Carmen Emanuela Georgescu; Stylianos Tsagarakis; Fredric Cohen; Maria Fleseriu

doi:10.1007/s11102-022-01263-7

Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)

Rosario Pivonello, Sabina Zacharieva, Atanaska Elenkova, Miklós Tóth, Ilan Shimon, Antonio Stigliano, Corin Badiu, Thierry Brue, Carmen Emanuela Georgescu, Stylianos Tsagarakis, Fredric Cohen, Maria Fleseriu

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Purpose: The efficacy of levoketoconazole for endogenous Cushing’s syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. Methods: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14–19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. Results: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: − 54.5% (95% CI − 75.7, − 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). Conclusions: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing’s syndrome. No new risks of levoketoconazole treatment were identified.

Original language	English (US)
Pages (from-to)	911-926
Number of pages	16
Journal	Pituitary
Volume	25
Issue number	6
DOIs	https://doi.org/10.1007/s11102-022-01263-7
State	Published - Dec 2022

Keywords

Cushing’s disease
Cushing’s syndrome
Hypercortisolism
Levoketoconazole
Placebo
Steroidogenesis inhibitor

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Endocrinology

Access to Document

10.1007/s11102-022-01263-7

Cite this

Pivonello, R., Zacharieva, S., Elenkova, A., Tóth, M., Shimon, I., Stigliano, A., Badiu, C., Brue, T., Georgescu, C. E., Tsagarakis, S., Cohen, F., & Fleseriu, M. (2022). Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary, 25(6), 911-926. https://doi.org/10.1007/s11102-022-01263-7

Pivonello, R, Zacharieva, S, Elenkova, A, Tóth, M, Shimon, I, Stigliano, A, Badiu, C, Brue, T, Georgescu, CE, Tsagarakis, S, Cohen, F & Fleseriu, M 2022, 'Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)', Pituitary, vol. 25, no. 6, pp. 911-926. https://doi.org/10.1007/s11102-022-01263-7

@article{b452ed179c8f424faa16ccb42fb2192e,

title = "Levoketoconazole in the treatment of patients with endogenous Cushing{\textquoteright}s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)",

abstract = "Purpose: The efficacy of levoketoconazole for endogenous Cushing{\textquoteright}s syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. Methods: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14–19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. Results: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: − 54.5% (95% CI − 75.7, − 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). Conclusions: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing{\textquoteright}s syndrome. No new risks of levoketoconazole treatment were identified.",

keywords = "Cushing{\textquoteright}s disease, Cushing{\textquoteright}s syndrome, Hypercortisolism, Levoketoconazole, Placebo, Steroidogenesis inhibitor",

author = "Rosario Pivonello and Sabina Zacharieva and Atanaska Elenkova and Mikl{\'o}s T{\'o}th and Ilan Shimon and Antonio Stigliano and Corin Badiu and Thierry Brue and Georgescu, {Carmen Emanuela} and Stylianos Tsagarakis and Fredric Cohen and Maria Fleseriu",

note = "Funding Information: The authors thank the site investigators, study coordinators, clinical staff, and patients who participated in the study. Medical editorial assistance was provided under the direction of the authors by Nancy Holland, PhD, Synchrony Medical Communications, LLC, West Chester, PA; funding for this support was provided by Strongbridge Biopharma (now Xeris Biopharma). LOGICS Investigator List Principal investigators (N = number of patients enrolled in the study for each site): Bulgaria : Zdravko Kamenov (Clinic of Endocrinology, Medical University of Sofia; N = 1); Maria Orbetzova (Sveti Georgy University Hospital; N = 1); Sabina Zacharieva (Acad. Ivan Penchev; N = 8); Denmark : Ulla Feldt-Rasmussen (Rigshospitalet, Copenhagen University Hospital; N = 0); France : Thierry Brue (H{\^o}pital de la CONCEPTION Service d{\textquoteright}Endocrinologie, Diabete et Maladies Metaboliques; N = 3); Greece : Fotini Adamidou (Hippokration General Hospital; N = 2); Gregory Kaltsas (National and Kapodistrian University of Athens-Laiko General Hospital; N = 0); Theodora Kounadi (General Hospital of Athens G. Gennimatas; N = 1); Stylianos Tsagarakis (Evangelismos Hospital, Athens; N = 3); Stelios Tigas (University Hospital of Ioannina, Department of Endocrinology; N = 0); Hungary : Mikl{\'o}s T{\'o}th (Semmelweis University; N = 5); Israel : Yona Greenman (Sourasky Medical Center; N = 1); Leonard Saiegh (Bnai Zion Medical Center Institute of Endocrinology and Metabolism; N = 1); Ilan Shimon (Institute of Endocrinology and Metabolism, Rabin Medical Center, Beilinson Campus; N = 5); Italy : Giorgio Arnaldi (Azienda Ospedaliera—Universitaria Ancona; N = 2); Salvatore Cannavo (UOC di Endocrinologia, Dipartimento di Medicina, AOU Policlinico G. Martino; N = 1); Diego Ferone (University of Genova, IRCCS AOU San Martino-IST; N = 1); Roberta Giordano (Azienda Ospedaliero—Universitaria Citt{\`a} della Salute e della Scienza di Torino; N = 2); Rosario Pivonello (University of Naples Federico II; N = 6); Alfredo Pontecorvi (Policlinico Universitario Agostino Gemelli; N = 0); Antonio Stigliano (Sant'Andrea Hospital, University of Rome {"}Sapienza,{"} Rome; N = 4); Netherlands : Nienke Biermasz (Leiden University Medical Center; N = 0); Richard Feelders (Polikliniek Endocrinologie, Erasmus MC; N = 2); Poland : Barbara Jarzab (Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, aria Sklodowska-Curie Memorial Institute, N = 0); Magdalena Stasiak (Instytut Centrum Zdrowia Matki Polki; N = 1); Przemyslaw Witek (Outpatient Clinic: Reuma Centrum; N = 0); Romania : Corin Badiu (National Institute of Endocrinology CI Parhon, Bucharest; N = 4); Melania-Olga Balas (Spitalul Clinic Judetean de Urgenta Pius Brinzeu Timisoara, Spitalul Clinic Judetean de Urgenta; N = 0); Carmen Georgescu (Iuliu Ha{\c t}ieganu University of Medicine and Pharmacy, Cluj-Napoca; N = 3); Ionela Pascanu (Universitatea de Medicina si Farmacie Tirgu Mures, Spitalul Clinic Judetean Mures; N = 2); Spain : Carmen Fajardo (Hospital Universidad de la Ribera; N = 0); Manuel Luque Ram{\'i}rez (Hospital Universitario Ram{\'o}n y Cajal, Endocrinology and Nutrition; N = 2); USA : John Carmichael (University of Southern California; N = 1); Tobias Else (University of Michigan Comprehensive Cancer Center, Ann Arbor; N = 1); Maria Fleseriu (Oregon Health and Science University; N = 3); Eliza Geer (Memorial Sloan-Kettering Cancer Center; N = 2); Murray Gordon (West Penn Allegheny Health System; N = 2); Anthony Heaney (University of California, Los Angeles, School of Medicine; N = 2); Wenyu Huang (Northwestern University, Feinberg School of Medicine; N = 1); Adriana Ioachimescu (Emory University Hospital; N = 1); Terri Jerkins (Midstate Endocrine Associates, Nashville; N = 0); Sam Lerman (The Center for Diabetes and Endocrine Care – Hollywood; N = 1); Ning-Ai Liu (Cedars-Sinai Medical Center; N = 0); Gabrielle Page-Wilson (Columbia University Medical Center; N = 1); Roberto Salvatori (Johns Hopkins University; N = 1); Julie Silverstein (Washington University School of Medicine in St. Louis; N = 2). Funding Information: The authors thank the site investigators, study coordinators, clinical staff, and patients who participated in the study. Medical editorial assistance was provided under the direction of the authors by Nancy Holland, PhD, Synchrony Medical Communications, LLC, West Chester, PA; funding for this support was provided by Strongbridge Biopharma (now Xeris Biopharma). LOGICS Investigator List Principal investigators (N = number of patients enrolled in the study for each site): Bulgaria : Zdravko Kamenov (Clinic of Endocrinology, Medical University of Sofia; N = 1); Maria Orbetzova (Sveti Georgy University Hospital; N = 1); Sabina Zacharieva (Acad. Ivan Penchev; N = 8); Denmark : Ulla Feldt-Rasmussen (Rigshospitalet, Copenhagen University Hospital; N = 0); France : Thierry Brue (H{\^o}pital de la CONCEPTION Service d{\textquoteright}Endocrinologie, Diabete et Maladies Metaboliques; N = 3); Greece : Fotini Adamidou (Hippokration General Hospital; N = 2); Gregory Kaltsas (National and Kapodistrian University of Athens-Laiko General Hospital; N = 0); Theodora Kounadi (General Hospital of Athens G. Gennimatas; N = 1); Stylianos Tsagarakis (Evangelismos Hospital, Athens; N = 3); Stelios Tigas (University Hospital of Ioannina, Department of Endocrinology; N = 0); Hungary : Mikl{\'o}s T{\'o}th (Semmelweis University; N = 5); Israel : Yona Greenman (Sourasky Medical Center; N = 1); Leonard Saiegh (Bnai Zion Medical Center Institute of Endocrinology and Metabolism; N = 1); Ilan Shimon (Institute of Endocrinology and Metabolism, Rabin Medical Center, Beilinson Campus; N = 5); Italy : Giorgio Arnaldi (Azienda Ospedaliera—Universitaria Ancona; N = 2); Salvatore Cannavo (UOC di Endocrinologia, Dipartimento di Medicina, AOU Policlinico G. Martino; N = 1); Diego Ferone (University of Genova, IRCCS AOU San Martino-IST; N = 1); Roberta Giordano (Azienda Ospedaliero—Universitaria Citt{\`a} della Salute e della Scienza di Torino; N = 2); Rosario Pivonello (University of Naples Federico II; N = 6); Alfredo Pontecorvi (Policlinico Universitario Agostino Gemelli; N = 0); Antonio Stigliano (Sant'Andrea Hospital, University of Rome {"}Sapienza,{"} Rome; N = 4); Netherlands : Nienke Biermasz (Leiden University Medical Center; N = 0); Richard Feelders (Polikliniek Endocrinologie, Erasmus MC; N = 2); Poland : Barbara Jarzab (Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, aria Sklodowska-Curie Memorial Institute, N = 0); Magdalena Stasiak (Instytut Centrum Zdrowia Matki Polki; N = 1); Przemyslaw Witek (Outpatient Clinic: Reuma Centrum; N = 0); Romania : Corin Badiu (National Institute of Endocrinology CI Parhon, Bucharest; N = 4); Melania-Olga Balas (Spitalul Clinic Judetean de Urgenta Pius Brinzeu Timisoara, Spitalul Clinic Judetean de Urgenta; N = 0); Carmen Georgescu (Iuliu Ha{\c t}ieganu University of Medicine and Pharmacy, Cluj-Napoca; N = 3); Ionela Pascanu (Universitatea de Medicina si Farmacie Tirgu Mures, Spitalul Clinic Judetean Mures; N = 2); Spain : Carmen Fajardo (Hospital Universidad de la Ribera; N = 0); Manuel Luque Ram{\'i}rez (Hospital Universitario Ram{\'o}n y Cajal, Endocrinology and Nutrition; N = 2); USA : John Carmichael (University of Southern California; N = 1); Tobias Else (University of Michigan Comprehensive Cancer Center, Ann Arbor; N = 1); Maria Fleseriu (Oregon Health and Science University; N = 3); Eliza Geer (Memorial Sloan-Kettering Cancer Center; N = 2); Murray Gordon (West Penn Allegheny Health System; N = 2); Anthony Heaney (University of California, Los Angeles, School of Medicine; N = 2); Wenyu Huang (Northwestern University, Feinberg School of Medicine; N = 1); Adriana Ioachimescu (Emory University Hospital; N = 1); Terri Jerkins (Midstate Endocrine Associates, Nashville; N = 0); Sam Lerman (The Center for Diabetes and Endocrine Care – Hollywood; N = 1); Ning-Ai Liu (Cedars-Sinai Medical Center; N = 0); Gabrielle Page-Wilson (Columbia University Medical Center; N = 1); Roberto Salvatori (Johns Hopkins University; N = 1); Julie Silverstein (Washington University School of Medicine in St. Louis; N = 2). Funding Information: RP reports receiving research support to Federico II University of Naples as a principal investigator for clinical trials from Corcept Therapeutics, HRA Pharma, Novartis, Recordati, and Xeris Biopharma/Strongbridge Biopharma; receiving different research support to Federico II University of Naples from Novartis and Xeris/Strongbridge; and receiving occassional consulting honoraria from Corcept Therapeutics, HRA Pharma, Novartis, Recordati, and Xeris/Strongbridge. SZ reports receiving consulting honoraria from Novartis. AE reports serving as the principal investigator/sub-investigator of clinical trials for Corcept Therapeutics and Novartis; and receiving consulting honoraria from Novartis. MT reports serving as the principal investigator of clinical trials for Corcept Therapeutics, HRA Pharma, Novartis, and Xeris/Strongbridge; serving as an occasional scientific consultant to HRA Pharma and Recordati; and receiving speaker{\textquoteright}s fees from Medis, Novartis, and Xeris/Strongbridge. IS reports receiving research grants, consulting, and lectureship fees from Medison Pharma, Novartis International, and Pfizer. AS reports receiving no grants or consulting honoraria from pharmaceutical companies. CB reports serving as the principal investigator of research grants from Novo Nordisk and Xeris/Strongbridge; and receiving consulting honoraria from Ipsen. TB reports serving as a clinical trial investigator for Novartis and Xeris/Strongbridge; receiving research grants from Ipsen and Pfizer; and serving as an advisory board member or receiving speaker{\textquoteright}s fees from Ipsen, Novartis, Pfizer, and Xeris/Strongbridge. CEG reports serving as the principal investigator of clinical trials for HRA Pharma and Xeris/Strongbridge. ST reports receiving research and travel grants and consulting honoraria from Novartis; and receiving consulting honoraria from Recordati. FC is a former employee of Strongbridge Biopharma/Xeris Pharma and reports receiving consulting fees from Xeris. MF reports serving as an investigator with research grants to OHSU from Novartis, Recordati, and Xeris/Strongbridge; serving as an occasional scientific consultant to HRA Pharma, Recordati, Sparrow, and Xeris/Strongbridge; and is on the Editorial Board of Pituitary. Funding Information: Open access funding provided by Universit{\`a} degli Studi di Napoli Federico II within the CRUI-CARE Agreement. The study was funded by Cortendo AB (a subsidiary of Strongbridge Biopharma [now Xeris Biopharma]). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1007/s11102-022-01263-7",

language = "English (US)",

volume = "25",

pages = "911--926",

journal = "Pituitary",

issn = "1386-341X",

publisher = "Kluwer Academic Publishers",

number = "6",

}

TY - JOUR

T1 - Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome

T2 - a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)

AU - Pivonello, Rosario

AU - Zacharieva, Sabina

AU - Elenkova, Atanaska

AU - Tóth, Miklós

AU - Shimon, Ilan

AU - Stigliano, Antonio

AU - Badiu, Corin

AU - Brue, Thierry

AU - Georgescu, Carmen Emanuela

AU - Tsagarakis, Stylianos

AU - Cohen, Fredric

AU - Fleseriu, Maria

N1 - Funding Information: The authors thank the site investigators, study coordinators, clinical staff, and patients who participated in the study. Medical editorial assistance was provided under the direction of the authors by Nancy Holland, PhD, Synchrony Medical Communications, LLC, West Chester, PA; funding for this support was provided by Strongbridge Biopharma (now Xeris Biopharma). LOGICS Investigator List Principal investigators (N = number of patients enrolled in the study for each site): Bulgaria : Zdravko Kamenov (Clinic of Endocrinology, Medical University of Sofia; N = 1); Maria Orbetzova (Sveti Georgy University Hospital; N = 1); Sabina Zacharieva (Acad. Ivan Penchev; N = 8); Denmark : Ulla Feldt-Rasmussen (Rigshospitalet, Copenhagen University Hospital; N = 0); France : Thierry Brue (Hôpital de la CONCEPTION Service d’Endocrinologie, Diabete et Maladies Metaboliques; N = 3); Greece : Fotini Adamidou (Hippokration General Hospital; N = 2); Gregory Kaltsas (National and Kapodistrian University of Athens-Laiko General Hospital; N = 0); Theodora Kounadi (General Hospital of Athens G. Gennimatas; N = 1); Stylianos Tsagarakis (Evangelismos Hospital, Athens; N = 3); Stelios Tigas (University Hospital of Ioannina, Department of Endocrinology; N = 0); Hungary : Miklós Tóth (Semmelweis University; N = 5); Israel : Yona Greenman (Sourasky Medical Center; N = 1); Leonard Saiegh (Bnai Zion Medical Center Institute of Endocrinology and Metabolism; N = 1); Ilan Shimon (Institute of Endocrinology and Metabolism, Rabin Medical Center, Beilinson Campus; N = 5); Italy : Giorgio Arnaldi (Azienda Ospedaliera—Universitaria Ancona; N = 2); Salvatore Cannavo (UOC di Endocrinologia, Dipartimento di Medicina, AOU Policlinico G. Martino; N = 1); Diego Ferone (University of Genova, IRCCS AOU San Martino-IST; N = 1); Roberta Giordano (Azienda Ospedaliero—Universitaria Città della Salute e della Scienza di Torino; N = 2); Rosario Pivonello (University of Naples Federico II; N = 6); Alfredo Pontecorvi (Policlinico Universitario Agostino Gemelli; N = 0); Antonio Stigliano (Sant'Andrea Hospital, University of Rome "Sapienza," Rome; N = 4); Netherlands : Nienke Biermasz (Leiden University Medical Center; N = 0); Richard Feelders (Polikliniek Endocrinologie, Erasmus MC; N = 2); Poland : Barbara Jarzab (Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, aria Sklodowska-Curie Memorial Institute, N = 0); Magdalena Stasiak (Instytut Centrum Zdrowia Matki Polki; N = 1); Przemyslaw Witek (Outpatient Clinic: Reuma Centrum; N = 0); Romania : Corin Badiu (National Institute of Endocrinology CI Parhon, Bucharest; N = 4); Melania-Olga Balas (Spitalul Clinic Judetean de Urgenta Pius Brinzeu Timisoara, Spitalul Clinic Judetean de Urgenta; N = 0); Carmen Georgescu (Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca; N = 3); Ionela Pascanu (Universitatea de Medicina si Farmacie Tirgu Mures, Spitalul Clinic Judetean Mures; N = 2); Spain : Carmen Fajardo (Hospital Universidad de la Ribera; N = 0); Manuel Luque Ramírez (Hospital Universitario Ramón y Cajal, Endocrinology and Nutrition; N = 2); USA : John Carmichael (University of Southern California; N = 1); Tobias Else (University of Michigan Comprehensive Cancer Center, Ann Arbor; N = 1); Maria Fleseriu (Oregon Health and Science University; N = 3); Eliza Geer (Memorial Sloan-Kettering Cancer Center; N = 2); Murray Gordon (West Penn Allegheny Health System; N = 2); Anthony Heaney (University of California, Los Angeles, School of Medicine; N = 2); Wenyu Huang (Northwestern University, Feinberg School of Medicine; N = 1); Adriana Ioachimescu (Emory University Hospital; N = 1); Terri Jerkins (Midstate Endocrine Associates, Nashville; N = 0); Sam Lerman (The Center for Diabetes and Endocrine Care – Hollywood; N = 1); Ning-Ai Liu (Cedars-Sinai Medical Center; N = 0); Gabrielle Page-Wilson (Columbia University Medical Center; N = 1); Roberto Salvatori (Johns Hopkins University; N = 1); Julie Silverstein (Washington University School of Medicine in St. Louis; N = 2). Funding Information: The authors thank the site investigators, study coordinators, clinical staff, and patients who participated in the study. Medical editorial assistance was provided under the direction of the authors by Nancy Holland, PhD, Synchrony Medical Communications, LLC, West Chester, PA; funding for this support was provided by Strongbridge Biopharma (now Xeris Biopharma). LOGICS Investigator List Principal investigators (N = number of patients enrolled in the study for each site): Bulgaria : Zdravko Kamenov (Clinic of Endocrinology, Medical University of Sofia; N = 1); Maria Orbetzova (Sveti Georgy University Hospital; N = 1); Sabina Zacharieva (Acad. Ivan Penchev; N = 8); Denmark : Ulla Feldt-Rasmussen (Rigshospitalet, Copenhagen University Hospital; N = 0); France : Thierry Brue (Hôpital de la CONCEPTION Service d’Endocrinologie, Diabete et Maladies Metaboliques; N = 3); Greece : Fotini Adamidou (Hippokration General Hospital; N = 2); Gregory Kaltsas (National and Kapodistrian University of Athens-Laiko General Hospital; N = 0); Theodora Kounadi (General Hospital of Athens G. Gennimatas; N = 1); Stylianos Tsagarakis (Evangelismos Hospital, Athens; N = 3); Stelios Tigas (University Hospital of Ioannina, Department of Endocrinology; N = 0); Hungary : Miklós Tóth (Semmelweis University; N = 5); Israel : Yona Greenman (Sourasky Medical Center; N = 1); Leonard Saiegh (Bnai Zion Medical Center Institute of Endocrinology and Metabolism; N = 1); Ilan Shimon (Institute of Endocrinology and Metabolism, Rabin Medical Center, Beilinson Campus; N = 5); Italy : Giorgio Arnaldi (Azienda Ospedaliera—Universitaria Ancona; N = 2); Salvatore Cannavo (UOC di Endocrinologia, Dipartimento di Medicina, AOU Policlinico G. Martino; N = 1); Diego Ferone (University of Genova, IRCCS AOU San Martino-IST; N = 1); Roberta Giordano (Azienda Ospedaliero—Universitaria Città della Salute e della Scienza di Torino; N = 2); Rosario Pivonello (University of Naples Federico II; N = 6); Alfredo Pontecorvi (Policlinico Universitario Agostino Gemelli; N = 0); Antonio Stigliano (Sant'Andrea Hospital, University of Rome "Sapienza," Rome; N = 4); Netherlands : Nienke Biermasz (Leiden University Medical Center; N = 0); Richard Feelders (Polikliniek Endocrinologie, Erasmus MC; N = 2); Poland : Barbara Jarzab (Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, aria Sklodowska-Curie Memorial Institute, N = 0); Magdalena Stasiak (Instytut Centrum Zdrowia Matki Polki; N = 1); Przemyslaw Witek (Outpatient Clinic: Reuma Centrum; N = 0); Romania : Corin Badiu (National Institute of Endocrinology CI Parhon, Bucharest; N = 4); Melania-Olga Balas (Spitalul Clinic Judetean de Urgenta Pius Brinzeu Timisoara, Spitalul Clinic Judetean de Urgenta; N = 0); Carmen Georgescu (Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca; N = 3); Ionela Pascanu (Universitatea de Medicina si Farmacie Tirgu Mures, Spitalul Clinic Judetean Mures; N = 2); Spain : Carmen Fajardo (Hospital Universidad de la Ribera; N = 0); Manuel Luque Ramírez (Hospital Universitario Ramón y Cajal, Endocrinology and Nutrition; N = 2); USA : John Carmichael (University of Southern California; N = 1); Tobias Else (University of Michigan Comprehensive Cancer Center, Ann Arbor; N = 1); Maria Fleseriu (Oregon Health and Science University; N = 3); Eliza Geer (Memorial Sloan-Kettering Cancer Center; N = 2); Murray Gordon (West Penn Allegheny Health System; N = 2); Anthony Heaney (University of California, Los Angeles, School of Medicine; N = 2); Wenyu Huang (Northwestern University, Feinberg School of Medicine; N = 1); Adriana Ioachimescu (Emory University Hospital; N = 1); Terri Jerkins (Midstate Endocrine Associates, Nashville; N = 0); Sam Lerman (The Center for Diabetes and Endocrine Care – Hollywood; N = 1); Ning-Ai Liu (Cedars-Sinai Medical Center; N = 0); Gabrielle Page-Wilson (Columbia University Medical Center; N = 1); Roberto Salvatori (Johns Hopkins University; N = 1); Julie Silverstein (Washington University School of Medicine in St. Louis; N = 2). Funding Information: RP reports receiving research support to Federico II University of Naples as a principal investigator for clinical trials from Corcept Therapeutics, HRA Pharma, Novartis, Recordati, and Xeris Biopharma/Strongbridge Biopharma; receiving different research support to Federico II University of Naples from Novartis and Xeris/Strongbridge; and receiving occassional consulting honoraria from Corcept Therapeutics, HRA Pharma, Novartis, Recordati, and Xeris/Strongbridge. SZ reports receiving consulting honoraria from Novartis. AE reports serving as the principal investigator/sub-investigator of clinical trials for Corcept Therapeutics and Novartis; and receiving consulting honoraria from Novartis. MT reports serving as the principal investigator of clinical trials for Corcept Therapeutics, HRA Pharma, Novartis, and Xeris/Strongbridge; serving as an occasional scientific consultant to HRA Pharma and Recordati; and receiving speaker’s fees from Medis, Novartis, and Xeris/Strongbridge. IS reports receiving research grants, consulting, and lectureship fees from Medison Pharma, Novartis International, and Pfizer. AS reports receiving no grants or consulting honoraria from pharmaceutical companies. CB reports serving as the principal investigator of research grants from Novo Nordisk and Xeris/Strongbridge; and receiving consulting honoraria from Ipsen. TB reports serving as a clinical trial investigator for Novartis and Xeris/Strongbridge; receiving research grants from Ipsen and Pfizer; and serving as an advisory board member or receiving speaker’s fees from Ipsen, Novartis, Pfizer, and Xeris/Strongbridge. CEG reports serving as the principal investigator of clinical trials for HRA Pharma and Xeris/Strongbridge. ST reports receiving research and travel grants and consulting honoraria from Novartis; and receiving consulting honoraria from Recordati. FC is a former employee of Strongbridge Biopharma/Xeris Pharma and reports receiving consulting fees from Xeris. MF reports serving as an investigator with research grants to OHSU from Novartis, Recordati, and Xeris/Strongbridge; serving as an occasional scientific consultant to HRA Pharma, Recordati, Sparrow, and Xeris/Strongbridge; and is on the Editorial Board of Pituitary. Funding Information: Open access funding provided by Università degli Studi di Napoli Federico II within the CRUI-CARE Agreement. The study was funded by Cortendo AB (a subsidiary of Strongbridge Biopharma [now Xeris Biopharma]). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Purpose: The efficacy of levoketoconazole for endogenous Cushing’s syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. Methods: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14–19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. Results: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: − 54.5% (95% CI − 75.7, − 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). Conclusions: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing’s syndrome. No new risks of levoketoconazole treatment were identified.

AB - Purpose: The efficacy of levoketoconazole for endogenous Cushing’s syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. Methods: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14–19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. Results: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: − 54.5% (95% CI − 75.7, − 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). Conclusions: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing’s syndrome. No new risks of levoketoconazole treatment were identified.

KW - Cushing’s disease

KW - Cushing’s syndrome

KW - Hypercortisolism

KW - Levoketoconazole

KW - Placebo

KW - Steroidogenesis inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85136871434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85136871434&partnerID=8YFLogxK

U2 - 10.1007/s11102-022-01263-7

DO - 10.1007/s11102-022-01263-7

M3 - Article

C2 - 36085339

AN - SCOPUS:85136871434

SN - 1386-341X

VL - 25

SP - 911

EP - 926

JO - Pituitary

JF - Pituitary

IS - 6

ER -

Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)

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