A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing's Syndrome.

Endogenous Cushing's Syndrome Clinical Trial

Official title:

A Double-blind, Placebo-Controlled, Randomized Withdrawal Following Open Label Therapy Study to Assess the Safety and Efficacy of Levoketoconazole (2S, 4R-ketoconazole) in the Treatment of Endogenous Cushing's Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03277690
• Other study ID #: COR-2017-01
• Status: Completed
• Phase: Phase 3
• Start date: September 26, 2017
• Est. completion date: August 31, 2020

Study information

• Verified date: October 2022
• Source: Cortendo AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration study in subjects with endogenous Cushing's Syndrome (CS) previously treated with single-arm, open-label levoketoconazole that will assess efficacy, safety, tolerability, and pharmacokinetics of levoketoconazole.

Description:

This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration study in subjects with endogenous CS that will assess efficacy, safety, tolerability, and Pharmacokinetics (PK) of levoketoconazole. There are two populations (cohorts) of subjects: (1) subjects which were previous levoketoconazole study completers and (2) subjects that are levoketoconazole treatment naïve subjects.

Study methodology varies by cohort prior to randomization only. Following initial screening (washout as needed) and Dose Titration and Maintenance Periods, as applicable, this study will be conducted in two double-blind phases (a Withdrawal Phase and a Restoration Phase). The levoketoconazole-naïve cohort will need to go through the Dose Titration and Maintenance Phase. The longest anticipated total study participation duration is approximately 51 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 84
• Est. completion date: August 31, 2020
• Est. primary completion date: June 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

INCLUSION CRITERIA:

SONICS STUDY COMPLETERS:

Completed the final SONICS visit (M12) and have demonstrated maintenance of clinical response on a stable Therapeutic Dose of levoketoconazole for at least 12 weeks prior to study entry.

ALL OTHERS:

• Confirmed newly diagnosed, persistent or recurrent endogenous Cushing's syndrome of any etiology, except secondary to malignancy (including pituitary or adrenal carcinoma).

• Elevated mean 24-hour Urinary Free Cortisol (UFC) levels at least 1.5X upper limit of the normative range of the study's central laboratory assay and from a minimum of three measurements from adequately collected urine.

• Presence of abnormal values from at least one of these two diagnostic tests:

• Abnormal Dexamethasone Suppression Test (DST) OR

• Elevated late night salivary cortisol concentrations (at least two measurements) each greater than the upper limit of the study's central laboratory normative range

• Non-candidates for CS-specific surgery, refuse surgery or surgery will be delayed until after study completion and agree to complete this study prior to surgery.

• If post-surgical for CS-specific surgery, then no significant post-operative sequelae remain and the risk of such sequelae is considered negligible.

EXCLUSION CRITERIA:

Subjects will be excluded from the study if ANY of the following criteria are met (NOTE:

exclusion criteria apply to and must be assessed in both cohorts):

• Enrolled in SONICS but have not completed SONICS through Visit M12.

• Pseudo-Cushing's syndrome based on assessment of the Investigator.

• Cyclic Cushing's syndrome with multi-week periods of apparent spontaneous CS remission.

• Non-endogenous source of hypercortisolism, including pharmacological corticosteroids or ACTH.

• Radiotherapy of any modality directed against the source of hypercortisolism within the last 5 years.

• Treatment with mitotane within 6 months of enrollment.

• History of malignancy, including adrenal or pituitary carcinomas (other than low-risk, well-differentiated carcinomas of thyroid, breast or prostate that are very unlikely to require further treatment in the opinion of the treating physician, or squamous cell or basal cell carcinoma of the skin).

• Clinical or radiological signs of compression of the optic chiasm.

Related Conditions & MeSH terms

• Cushing Syndrome
• Endogenous Cushing's Syndrome
• Syndrome

Intervention

Drug:
• Levoketoconazole
During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily. During the double-blind Restoration Phase, patients will receive levoketoconazole plus placebo.
• Placebo
During the double-blind Withdrawal Phase, patients will receive placebo tablets. During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.

Locations

Country	Name	City	State
Bulgaria	Alexandovska University Hospital, Clinic of Endocrinology & Metabolic Diseases	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment "Aleksandrovska" EAD Clinic of Endocrinology and Metabolic Diseases	Sofia
Bulgaria	University Specialized Hospital for Active Treatment in Endocrinology (USHATE) I Klinika	Sofia
Denmark	Rigshospitalet, Copenhagen University Hospital, Endocrinology Department	Copenhagen
France	APHM Hôpital de la Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques	Marseille	Cedex 5
Greece	Evangelismos Athens General Hospital, Department of Endocrinology	Athens
Greece	General Hospital of Athens 'G. Gennimatas', Department of Endocrinology-Diabetes Centre	Athens
Greece	General Hospital of Athens 'Laiko', "National and Kapodistrian University of Athens Medical School Pathophysiology - Endocrinology"	Athens
Greece	University General Hospital of Ioannina, Department of Endocrinology	Ioánnina
Greece	Hippokration General Hospital, "Endocrinology and Diabetes Department	Thessaloníki
Hungary	Semmelweis Egyetem II. Belgyógyászati Klinika A.épület I.emelet ODM-labor	Budapest
Israel	Bnai Zion Medical Center, Institute of Endocrinology	Haifa
Israel	Rabin Medical Center- Beilinson Hospital, "Institute of Endocrinology & Metabolism, Beilinson Campus"	Petach Tikva
Israel	Tel-Aviv Sourasky Medical Center Institute of Endocrinology, Metabolism and Hypertension	Tel Aviv
Italy	Clinica di Endocrinologia e malattie del Metabolismo, Dipartimento Specialità Mediche	Ancona
Italy	University of Genova, Department of Internal Medicine & Medical Specialties (DiMI)	Genova
Italy	AOU Policlinico G. Martino Sezione di Endocrinologia	Messina
Italy	AOU Federico II, Sezione di Endocrinologia (Edificio 1, Secondo Piano)	Napoli
Italy	Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Endocrinology	Roma
Italy	Policlinico Universitario Sant'Andrea, Scienze Mediche	Roma
Italy	AOU Citta della Salure e della Scienza SC Endocrinologia, Diabetologia e Metabolismo	Torino
Netherlands	Leiden University, Leiden University Medical Center, Department of Endocrinology	Leiden
Netherlands	Erasmus Medical Center, Department of Internal Medicine	Rotterdam
Poland	Maria Sklodowska-Curie Memorial Institute - Cancer Center Gliwice Branch, Nuclear Medicine and Endocrine Oncology Department	Gliwice
Poland	Instytut Centrum Zdrowia Matki Polki, Oddzial Endokrynologii i Chorób Metabolicznych	Lódz
Poland	Wojskowy Instytut Medyczny, Klinika Gastroenterologii, Endokrynologii I Chorob Wewnetrznych	Warsaw
Romania	Institutul National de Endocrinologie C.I. Parhon, Sectia Clinica de Endocrinologie II, Patologia tiroidei de corelatie	Bucuresti
Romania	Spitalul Clinic Judetean de Urgenta Cluj-Napoca, Sectia Clinica Endocrinologie	Cluj-Napoca
Romania	Spitalul Clinic Judetean Mures, Compartimentul de Endocrinologie	Târgu-Mures	Mures
Romania	Spitalul Clinic Judetean de Urgenta "Pius Brinzeu", Departamentul de Endocrinologie	Timisoara	Timis
Spain	Hospital Universidad De La Ribera, Endocrinologia	Alzira	Valencia
Spain	Hospital Universitario Ramón y Cajal, Endocrinology and Nutrition	Madrid
United States	University of Michigan, Comprehensive Endocrine Research, Internal Medicine - MEND	Ann Arbor	Michigan
United States	Emory University, Neurosurgery	Atlanta	Georgia
United States	Johns Hopkins University, Endocrinology Department	Baltimore	Maryland
United States	Northwestern University, Medicine - Endocrinology	Chicago	Illinois
United States	The Center for Diabetes and Endocrine Care	Fort Lauderdale	Florida
United States	Cedars-Sinai Medical Center, Cedars-Sinai Pituitary Center	Los Angeles	California
United States	Keck Medical Center University of Southern California HCII, Internal Medicine - Keck Hospital	Los Angeles	California
United States	UCLA School of Medicine, Medicine/Endocrinology Department	Los Angeles	California
United States	Columbia University, College of P&S Medicine/Neuro-endocrine Unit	New York	New York
United States	Memorial Sloan Kettering Cancer Center, Endocrinology	New York	New York
United States	Allegheny Neuroendocrinology Center, West Penn Allegheny Health System	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University, Neurological Surgery	Portland	Oregon
United States	Washington University School of Medicine, Endocrinology	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Cortendo AB

Countries where clinical trial is conducted

United States,  Bulgaria,  Denmark,  France,  Greece,  Hungary,  Israel,  Italy,  Netherlands,  Poland,  Romania,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects With Loss of Therapeutic Response to Levoketoconazole Upon Withdrawing to Placebo Compared With the Proportion of Subjects With Loss of Therapeutic Response Upon Continuing Treatment With Levoketoconazole.	Urinary free cortisol (UFC) level measurement: Loss of therapeutic response is inferred based on mUFC from three 24-hour UFC measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when: (1) mUFC is above 1.5X the ULN of the central laboratory's reference range, OR (2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is above the ULN (i.e. >1.0X ULN)1, OR (3) an early rescue criterion is met.	max. 9.5 weeks