Clinical trial NCT03277690: A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing's Syndrome.
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Endogenous Cushing's Syndrome
Keywords: Cushing Syndrome, Adrenocortical Hyperfunction
Lead sponsor: Cortendo AB
Sponsor class: INDUSTRY
First posted: 2017-09-11
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: max. 9.5 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Keck Medical Center University of Southern California HCII, Internal Medicine - Keck Hospital
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center, Cedars-Sinai Pituitary Center
state: California
city: Los Angeles
country: United States
facility: UCLA School of Medicine, Medicine/Endocrinology Department
state: California
city: Fort Lauderdale
country: United States
facility: The Center for Diabetes and Endocrine Care
state: Florida
city: Atlanta
country: United States
facility: Emory University, Neurosurgery
state: Georgia
city: Chicago
country: United States
facility: Northwestern University, Medicine - Endocrinology
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University, Endocrinology Department
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan, Comprehensive Endocrine Research, Internal Medicine - MEND
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine, Endocrinology
state: Missouri
city: New York
country: United States
facility: Columbia University, College of P&S Medicine/Neuro-endocrine Unit
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center, Endocrinology
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University, Neurological Surgery
state: Oregon
city: Pittsburgh
country: United States
facility: Allegheny Neuroendocrinology Center, West Penn Allegheny Health System
state: Pennsylvania
city: Sofia
country: Bulgaria
facility: Alexandovska University Hospital, Clinic of Endocrinology & Metabolic Diseases
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "Aleksandrovska" EAD Clinic of Endocrinology and Metabolic Diseases
city: Sofia
country: Bulgaria
facility: University Specialized Hospital for Active Treatment in Endocrinology (USHATE) I Klinika
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Copenhagen University Hospital, Endocrinology Department
city: Marseille
country: France
facility: APHM Hôpital de la Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques
state: Cedex 5
city: Athens
country: Greece
facility: Evangelismos Athens General Hospital, Department of Endocrinology
city: Athens
country: Greece
facility: General Hospital of Athens 'G. Gennimatas', Department of Endocrinology-Diabetes Centre
city: Athens
country: Greece
facility: General Hospital of Athens 'Laiko', "National and Kapodistrian University of Athens Medical School Pathophysiology - Endocrinology"
city: Ioánnina
country: Greece
facility: University General Hospital of Ioannina, Department of Endocrinology
city: Thessaloníki
country: Greece
facility: Hippokration General Hospital, "Endocrinology and Diabetes Department
city: Budapest
country: Hungary
facility: Semmelweis Egyetem II. Belgyógyászati Klinika A.épület I.emelet ODM-labor
city: Haifa
country: Israel
facility: Bnai Zion Medical Center, Institute of Endocrinology
city: Petach Tikva
country: Israel
facility: Rabin Medical Center- Beilinson Hospital, "Institute of Endocrinology & Metabolism, Beilinson Campus"
city: Tel Aviv
country: Israel
facility: Tel-Aviv Sourasky Medical Center Institute of Endocrinology, Metabolism and Hypertension
city: Ancona
country: Italy
facility: Clinica di Endocrinologia e malattie del Metabolismo, Dipartimento Specialità Mediche
city: Genova
country: Italy
facility: University of Genova, Department of Internal Medicine & Medical Specialties (DiMI)
city: Messina
country: Italy
facility: AOU Policlinico G. Martino Sezione di Endocrinologia
city: Napoli
country: Italy
facility: AOU Federico II, Sezione di Endocrinologia (Edificio 1, Secondo Piano)
city: Roma
country: Italy
facility: Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Endocrinology
city: Roma
country: Italy
facility: Policlinico Universitario Sant'Andrea, Scienze Mediche
city: Torino
country: Italy
facility: AOU Citta della Salure e della Scienza SC Endocrinologia, Diabetologia e Metabolismo
city: Leiden
country: Netherlands
facility: Leiden University, Leiden University Medical Center, Department of Endocrinology
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center, Department of Internal Medicine
city: Gliwice
country: Poland
facility: Maria Sklodowska-Curie Memorial Institute - Cancer Center Gliwice Branch, Nuclear Medicine and Endocrine Oncology Department
city: Warsaw
country: Poland
facility: Wojskowy Instytut Medyczny, Klinika Gastroenterologii, Endokrynologii I Chorob Wewnetrznych
city: Łódź
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki, Oddział Endokrynologii i Chorób Metabolicznych
city: Târgu-Mureş
country: Romania
facility: Spitalul Clinic Judetean Mures, Compartimentul de Endocrinologie
state: Mures
city: Timişoara
country: Romania
facility: Spitalul Clinic Judetean de Urgenta "Pius Brinzeu", Departamentul de Endocrinologie
state: Timis
city: Bucuresti
country: Romania
facility: Institutul National de Endocrinologie C.I. Parhon, Sectia Clinica de Endocrinologie II, Patologia tiroidei de corelatie
city: Cluj-Napoca
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Cluj-Napoca, Sectia Clinica Endocrinologie
city: Alzira
country: Spain
facility: Hospital Universidad De La Ribera, Endocrinologia
state: Valencia
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal, Endocrinology and Nutrition
Study officials:
affiliation: Cortendo AB
name: Xavier Valencia, MD
role: STUDY_DIRECTOR
References: