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

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

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.

Study Overview

• Status: Completed
• Conditions: Endogenous Cushing's Syndrome
• Intervention / Treatment: Drug: Levoketoconazole; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria, 1431
    • Alexandovska University Hospital, Clinic of Endocrinology & Metabolic Diseases
  • Sofia, Bulgaria, 1431
    • University Multiprofile Hospital for Active Treatment "Aleksandrovska" EAD Clinic of Endocrinology and Metabolic Diseases
  • Sofia, Bulgaria, 1431
    • University Specialized Hospital for Active Treatment in Endocrinology (USHATE) I Klinika
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet, Copenhagen University Hospital, Endocrinology Department
• France
  • Cedex 5
    • Marseille, Cedex 5, France, 13385
      • APHM Hôpital de la Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques
• Greece
  • Athens, Greece, 10676
    • Evangelismos Athens General Hospital, Department of Endocrinology
  • Athens, Greece, 11527
    • General Hospital of Athens 'G. Gennimatas', Department of Endocrinology-Diabetes Centre
  • Athens, Greece, 11527
    • General Hospital of Athens 'Laiko', "National and Kapodistrian University of Athens Medical School Pathophysiology - Endocrinology"
  • Ioánnina, Greece, 45110
    • University General Hospital of Ioannina, Department of Endocrinology
  • Thessaloníki, Greece, 54642
    • Hippokration General Hospital, "Endocrinology and Diabetes Department
• Hungary
  • Budapest, Hungary, 1088
    • Semmelweis Egyetem II. Belgyógyászati Klinika A.épület I.emelet ODM-labor
• Israel
  • Haifa, Israel, 34802
    • Bnai Zion Medical Center, Institute of Endocrinology
  • Petach Tikva, Israel, 49100
    • Rabin Medical Center- Beilinson Hospital, "Institute of Endocrinology & Metabolism, Beilinson Campus"
  • Tel Aviv, Israel, 642-3906
    • Tel-Aviv Sourasky Medical Center Institute of Endocrinology, Metabolism and Hypertension
• Italy
  • Ancona, Italy, 60126
    • Clinica di Endocrinologia e malattie del Metabolismo, Dipartimento Specialità Mediche
  • Genova, Italy, 16132
    • University of Genova, Department of Internal Medicine & Medical Specialties (DiMI)
  • Messina, Italy, 98125
    • AOU Policlinico G. Martino Sezione di Endocrinologia
  • Napoli, Italy, 8031
    • AOU Federico II, Sezione di Endocrinologia (Edificio 1, Secondo Piano)
  • Roma, Italy, 00168
    • Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Endocrinology
  • Roma, Italy, 00189
    • Policlinico Universitario Sant'Andrea, Scienze Mediche
  • Torino, Italy, 10126
    • AOU Citta della Salure e della Scienza SC Endocrinologia, Diabetologia e Metabolismo
• Netherlands
  • Leiden, Netherlands, 2333ZA
    • Leiden University, Leiden University Medical Center, Department of Endocrinology
  • Rotterdam, Netherlands, 3015CE
    • Erasmus Medical Center, Department of Internal Medicine
• Poland
  • Gliwice, Poland, 44-101
    • Maria Sklodowska-Curie Memorial Institute - Cancer Center Gliwice Branch, Nuclear Medicine and Endocrine Oncology Department
  • Warsaw, Poland, 04-141
    • Wojskowy Instytut Medyczny, Klinika Gastroenterologii, Endokrynologii I Chorob Wewnetrznych
  • Łódź, Poland, 93-338
    • Instytut Centrum Zdrowia Matki Polki, Oddział Endokrynologii i Chorób Metabolicznych
• Romania
  • Bucuresti, Romania, 011863
    • Institutul National de Endocrinologie C.I. Parhon, Sectia Clinica de Endocrinologie II, Patologia tiroidei de corelatie
  • Cluj-Napoca, Romania, 400349
    • Spitalul Clinic Judetean de Urgenta Cluj-Napoca, Sectia Clinica Endocrinologie
  • Mures
    • Târgu-Mureş, Mures, Romania, 540072
      • Spitalul Clinic Judetean Mures, Compartimentul de Endocrinologie
  • Timis
    • Timişoara, Timis, Romania, 300723
      • Spitalul Clinic Judetean de Urgenta "Pius Brinzeu", Departamentul de Endocrinologie
• Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal, Endocrinology and Nutrition
  • Valencia
    • Alzira, Valencia, Spain, 46600
      • Hospital Universidad De La Ribera, Endocrinologia
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Keck Medical Center University of Southern California HCII, Internal Medicine - Keck Hospital
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center, Cedars-Sinai Pituitary Center
    • Los Angeles, California, United States, 90095
      • UCLA School of Medicine, Medicine/Endocrinology Department
  • Florida
    • Fort Lauderdale, Florida, United States, 33312
      • The Center for Diabetes and Endocrine Care
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University, Neurosurgery
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University, Medicine - Endocrinology
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University, Endocrinology Department
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan, Comprehensive Endocrine Research, Internal Medicine - MEND
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine, Endocrinology
  • New York
    • New York, New York, United States, 10032
      • Columbia University, College of P&S Medicine/Neuro-endocrine Unit
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center, Endocrinology
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University, Neurological Surgery
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Neuroendocrinology Center, West Penn Allegheny Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levoketoconazole; Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo	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.; Other Names: COR-003
Placebo Comparator: Placebo; Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole	Drug: Placebo; During the double-blind Withdrawal Phase, patients will receive placebo tablets. During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Cortendo AB

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2017
• Primary Completion (Actual): June 30, 2020
• Study Completion (Actual): August 31, 2020

Study Registration Dates

• First Submitted: September 7, 2017
• First Submitted That Met QC Criteria: September 7, 2017
• First Posted (Actual): September 11, 2017

Study Record Updates

• Last Update Posted (Actual): November 8, 2022
• Last Update Submitted That Met QC Criteria: October 13, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Cushing Syndrome, Adrenocortical Hyperfunction
• Additional Relevant MeSH Terms: Pathologic Processes; Endocrine System Diseases; Disease; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Syndrome; Cushing Syndrome
• Other Study ID Numbers: COR-2017-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No