Treatment for Endogenous Cushing's Syndrome

NCT01838551 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: COR-2012-01
• Study Type: interventional
• Target: 94
• Locations: 15 countries
• Sites: 42

Brief Summary

The primary objectives of this study are to evaluate the clinical responder rate, defined as the proportion of subjects with normal UFC after 6 months of treatment with COR-003 in the Maintenance Phase without dose increase, and to evaluate the range of effective doses in subjects with various levels of hypercortisolism.

Conditions

Endogenous Cushing's Syndrome

Keywords

Cushing's disease; ectopic ACTH; adrenal Cushing's

Outcome Measures

Primary Outcomes (1)

• Normalization in Urinary Free Cortisol in Patients With Endogenous Cushing's Syndrome.

  The response to COR-003 is defined as mean UFC concentration ≤ULN following 6 months of maintenance phase therapy without a prior dose increase during that phase. The proportion of responders at the End of Maintenance Phase visit, following 6 months of treatment in the Maintenance Phase, for all dose groups combined was estimated using a generalized linear model with repeated measurements based on a binomial distribution with a logit link function and with region (US vs. non-US), concurrent CS medical conditions (diabetes \[Yes/No\], hypertension \[Yes/No\]), age (rounded median split based on the ITT population), sex, disease duration (years), prior CS medication (Yes/No), prior radiation therapy (Yes/No) as Baseline covariates and visit as an independent factor. The least squares mean (LSMEAN) estimate of the UFC response after 6 months of treatment in the Maintenance Phase alongside its 95% Wald CI is presented.

  6 months of maintenance phase therapy without a prior dose increase during that phase

Study Arms (8)

Levoketoconazole DL0

EXPERIMENTAL

Levoketoconazole Tablets Dose Level 0 Once Daily

Drug: Levoketoconazole

Levoketoconazole DL1

EXPERIMENTAL

Levoketoconazole Tablets Dose Level 1 Twice Daily

Drug: Levoketoconazole

Levoketoconazole DL2

EXPERIMENTAL

Levoketoconazole Tablets Dose Level 1 Twice Daily

Drug: Levoketoconazole

Levoketoconazole DL3

EXPERIMENTAL

Levoketoconazole Tablets Dose Level 3 Twice Daily

Drug: Levoketoconazole

Levoketoconazole DL4

EXPERIMENTAL

Levoketoconazole Tablets Dose Level 4 Twice Daily

Drug: Levoketoconazole

Levoketoconazole DL5

EXPERIMENTAL

Levoketoconazole Tablets Dose Level 5 Twice Daily

Drug: Levoketoconazole

Levoketoconazole DL6

EXPERIMENTAL

Levoketoconazole Tablets Dose Level 6 Twice Daily

Drug: Levoketoconazole

Levoketoconazole DL7

EXPERIMENTAL

Levoketoconazole Tablets Dose Level 7 Twice Daily

Drug: Levoketoconazole

Interventions

Levoketoconazole DRUG

Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole

Also known as: COR-003

Levoketoconazole DL0; Levoketoconazole DL1; Levoketoconazole DL2; Levoketoconazole DL3; Levoketoconazole DL4; Levoketoconazole DL5; Levoketoconazole DL6; Levoketoconazole DL7

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥18 years of age
• Confirmed diagnosis of newly diagnosed, persistent or recurrent Cushing's disease (CD) or endogenous CS of other etiology if subjects are not candidates for surgery or radiotherapy within the 18 months after enrollment.
• Previous medical records will be collected and used to support the diagnosis of CD or endogenous CS of other etiology, including the following etiologies:
• Ectopic adrenocorticotropic hormone (ACTH) secretion, i.e. ACTH not of pituitary origin
• Ectopic corticotropin-releasing hormone (CRH) secretion
• Adrenal-dependent CS (i.e. adrenal adenoma (NOT carcinoma), adrenal hyperplasia, etc.)
• Etiology unknown.
• Must have elevated mean 24 hour UFC levels ≥1.5X ULN based on the normative range of the central lab assay and on a minimum of four measurements from adequately collected urine.
• In addition to elevated mean UFC, presence of abnormal values from one of the following tests:
• Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 micrograms/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior (if not conducted already in the diagnostic workup of the subject within the previous 2 months before start of Screening Phase; in that case previous test results and details of conduct will need to be available by the Baseline Visit)
• Elevated late night salivary cortisol concentrations (at least two measurements) \>ULN
• Previously irradiated subjects with CD or endogenous CS of other etiology will be allowed as long as the radiation treatment occurred \> 4 years ago and subjects have not exhibited evidence for improvement in their underlying CD for 6 months prior to the Screening visit. The total number of previously irradiated subjects enrolled in this study will not exceed 10.
• Subjects with CD or CS of other etiology who are not candidates for surgery, refuse surgery, or in whom surgery will be delayed for at least 18 months following enrollment. Subjects may be allowed to participate in the trial while awaiting surgery, but must agree to complete this study prior to surgery.
• Subjects on treatment for CD or endogenous CS of other etiology for whom treatment has been inadequate or not well tolerated must agree to minimum washout periods prior to the Baseline Visit as specified.

You may not qualify if:

• Subjects with Pseudo-Cushing's syndrome based on assessment of the Investigator.
• Subjects with cyclic CS based on assessment of the Investigator
• Subjects with a non-endogenous source of hypercortisolism such as exogenous source of glucocorticoids or therapeutic use of ACTH.
• Known inherited syndrome as the cause of hypercortisolism, including but not limited to multiple endocrine neoplasia Type 1, McCune Albright Syndrome and Carney Complex
• Subjects with adrenal carcinoma
• History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the Screening Phase.
• Subjects with QTc interval of \>470 msec during the Screening Phase.
• Pre-existing hepatic disease; subjects with mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic fatty liver disease \[NAFLD\] are allowed).
• History of documented or suspected drug-induced liver injury requiring drug discontinuation of ketoconazole or any azole antifungals.
• Subjects who receive any prohibited concomitant medication and cannot discontinue it safely prior to the Baseline Visit.

Sponsors & Collaborators

• Cortendo AB: lead

Study Sites (42)

UCLA School of Medicine

Los Angeles, California, 90095, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48109, United States

Location

University of New Mexico HSC

Albuquerque, New Mexico, 87131, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Allegheny Neuroendocrinology Center

Pittsburgh, Pennsylvania, 15212, United States

Location

University Hospitals Leuven Department of Endocrinology

Leuven, 3000, Belgium

Location

University Specialized Hospital for Active Treatment in Endocrinology (USHATE)

Sofia, 1431, Bulgaria

Location

St. Pauls Hospital/Vancouver General Hospital

Vancouver, British Columbia, V6Z 1Y6, Canada

Location

Vseobecna fakultni nemocnice v Praze - III. Interni klinika VFN a 1. LF UK

Prague, 128 08, Czechia

Location

Aarhus University Hospital

Aarhus, 8000, Denmark

Location

Rigshospitalet,Copenhagen University Hospital

Copenhagen, DK-2100, Denmark

Location

Hôpital de la CONCEPTION, Service d'Endocrinologie, Diabète et Maladies Métaboliques

Marseille, 13385, France

Location

Med Clinic I - University of Lueback

Lübeck, 23538, Germany

Location

Bnail Zion Medical Center Institute of Endocrinology & Metabolism

Haifa, 31048, Israel

Location

Institute of Endocrinology & Metabolism, Rabin Medical Center

Petah Tikva, 49100, Israel

Location

Sourasky Medical Center, Endocrinology & Metabolism

Tel Aviv, 64239, Israel

Location

Azienda Ospedaliera-Universitaria Ancona

Ancona, 60126, Italy

Location

UOC di Endocrinologia, Dipartimento di Medicina Clinica e Sperimentale

Messina, 98125, Italy

Location

Istituto Auxologico Italiano

Milan, 20149, Italy

Location

University of Naples Federico II

Naples, 80131, Italy

Location

SCDU Medicina Interna I Università di Torino Dipartimento di Scienze Cliniche e Biologiche

Orbassano, 10043, Italy

Location

University of Padua

Padua, 35128, Italy

Location

Institute of Medical Pathology

Roma, 00168, Italy

Location

Azienda Ospedaliero - Universitaria Città della Salute e della Scienza di Torino

Torino, 10126, Italy

Location

Policlinico GB Rossi

Verona, 37134, Italy

Location

Leiden University, Leiden University Medical Center, Dept. of Endocrinology

Leiden, 2333 ZA, Netherlands

Location

Erasmus MC, Dpt. Of Internal Medicine, Division of Endocrinology

Rotterdam, 3015 CE, Netherlands

Location

Instytut Centrum Zdrowia Matki Polki

Lodz, 93-338, Poland

Location

Terpa Sp.z.o.o

Lublin, 20-333, Poland

Location

Szpital Kliniczny im. Heliodora Swiecickiego

Poznan, 60-355, Poland

Location

Outpatient Clinic: Reuma Centrum

Warsaw, 04-305, Poland

Location

Samodzielny Publiczny Szpital Kliniczny Nr 1

Wroclaw, 50367, Poland

Location

Clinical Center of Serbia

Belgrade, 11000, Serbia

Location

Hospital Universidad De La Ribera

Alzira, Valencia, 46600, Spain

Location

Endocrinologia, Hospital Sant Pau,Universitat Autònoma de Barcelona

Barcelona, 08026, Spain

Location

Hospital Universitario Reina Sofía

Córdoba, 14004, Spain

Location

Bezmi Alem Vakıf Üniversitesi Endokrinoloji Bölümü Adnan

Istanbul, 34093, Turkey (Türkiye)

Location

Istanbul University Medical Faculty

Istanbul, 34303, Turkey (Türkiye)

Location

Related Publications (3)

• Fleseriu M, Pivonello R, Elenkova A, Salvatori R, Auchus RJ, Feelders RA, Geer EB, Greenman Y, Witek P, Cohen F, Biller BMK. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol. 2019 Nov;7(11):855-865. doi: 10.1016/S2213-8587(19)30313-4. Epub 2019 Sep 18.

  PMID: 31542384 RESULT

• Geer EB, Salvatori R, Elenkova A, Fleseriu M, Pivonello R, Witek P, Feelders RA, Bex M, Borresen SW, Puglisi S, Biller BMK, Cohen F, Pecori Giraldi F. Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome. Pituitary. 2021 Feb;24(1):104-115. doi: 10.1007/s11102-020-01103-6. Epub 2020 Nov 20.

  PMID: 33216275 RESULT

• Pivonello R, Elenkova A, Fleseriu M, Feelders RA, Witek P, Greenman Y, Geer EB, Perotti P, Saiegh L, Cohen F, Arnaldi G. Levoketoconazole in the Treatment of Patients With Cushing's Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study. Front Endocrinol (Lausanne). 2021 Apr 7;12:595894. doi: 10.3389/fendo.2021.595894. eCollection 2021.

  PMID: 33897615 DERIVED

MeSH Terms

Conditions

Pituitary ACTH Hypersecretion

Condition Hierarchy (Ancestors)

Hyperpituitarism; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Strongbridge Biopharma

f.cohen@strongbridgebio.com

14845890392

Study Officials

• Fredric J Cohen, MD

  Cortendo AB

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: A data integrity plan prevented the Sponsor from accessing summary efficacy data prior to locking the clinical database.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Dose titration

Study Record Dates

• First Submitted: April 19, 2013
• First Posted: April 24, 2013
• Study Start: August 1, 2014
• Primary Completion: April 1, 2018
• Study Completion: November 1, 2018
• Last Updated: April 19, 2021
• Results First Posted: April 19, 2021

Record last verified: 2021-03

Locations

TU (2); NL (2); DE (1); ES (3); BE (1); IL (3); US (9); CZ (1); CA (1); IT (9); FR (1); BU (1); SE (1); PL (5); DK (2)