Clinical trial NCT01838551: Treatment for Endogenous Cushing's Syndrome
Official title: An Open Label Study to Assess the Safety and Efficacy of COR-003 (Levoketoconazole) in the Treatment of Endogenous Cushing's Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Endogenous Cushing's Syndrome
Keywords: Cushing's disease
ectopic ACTH
adrenal Cushing's
Lead sponsor: Cortendo AB
Sponsor class: INDUSTRY
First posted: 2013-04-24
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose titration
Primary purpose: TREATMENT

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.

Detailed description: This is an open label, single arm study with a Screening Phase, a Dose Titration Phase, a 6-month Maintenance Phase, and a 6-month Extended Evaluation Phase designed to assess efficacy, safety, tolerability, and PK of COR-003 in subjects with endogenous CS.

Following an initial screening and washout period, as applicable, this study will be conducted in three treatment phases as follows:

* Dose Titration Phase: approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose). Dose titration will occur in increments of 150 mg with a starting dose of 150 mg twice daily (BID) over a period of approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose).
* Maintenance Phase: 6 months of treatment at the Therapeutic Dose following the Dose Titration Phase. Once the Therapeutic Dose has been reached and confirmed from the mean of a total of four adequately collected 24 hour urine collections for UFC measurements, subjects will enter into the Maintenance Phase of the study and will be asked to return to the clinic monthly for 6 months for assessment of efficacy and safety. During the Maintenance Phase, doses may not be increased to maintain UFC levels at or below ULN of the assay unless it is confirmed that a dose increase is deemed medically necessary at the discretion of the Investigator after discussion with the Medical Monitor. Prior to the End of Maintenance Phase Visit, four complete 24 hour urine collections will be obtained and subjects may enter the Extended Evaluation Phase.
* Extended Evaluation Phase: 6 months of continued treatment after the Maintenance Phase. In the 6-month Extended Evaluation Phase, subjects will return to the clinical site every 90 days (±14 days) for safety and efficacy evaluations.

Efficacy will be assessed primarily by measuring mean UFC concentrations at specified times as described in the clinical protocol. Safety will be assessed primarily by physical examinations with vital sign measurements, adverse events, clinical laboratory measures, electrocardiography, and pituitary MRI.

An independent Data Safety Monitoring Board (DSMB) will review the safety of the drug throughout the study. Membership of the DSMB is described in a Charter.

Eligibility criteria: Key Inclusion Criteria:

1. Male or female ≥18 years of age
2. Able to provide written informed consent prior to any study procedures being performed; eligible subjects must be able to understand the informed consent form prior to inclusion into the study.
3. 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.
4. 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.
5. 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
6. 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.
7. 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.
8. 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.

Key Exclusion Criteria

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

Primary outcomes:
measure: Normalization in Urinary Free Cortisol in Patients With Endogenous Cushing's Syndrome.
timeFrame: 6 months of maintenance phase therapy without a prior dose increase during that phase
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA School of Medicine
state: California
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Albuquerque
country: United States
facility: University of New Mexico HSC
state: New Mexico
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pittsburgh
country: United States
facility: Allegheny Neuroendocrinology Center
state: Pennsylvania
city: Leuven
country: Belgium
facility: University Hospitals Leuven Department of Endocrinology
city: Sofia
country: Bulgaria
facility: University Specialized Hospital for Active Treatment in Endocrinology (USHATE)
city: Vancouver
country: Canada
facility: St. Pauls Hospital/Vancouver General Hospital
state: British Columbia
city: Praha
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze - III. Interni klinika VFN a 1. LF UK
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet,Copenhagen University Hospital
city: Marseille Cedex
country: France
facility: Hôpital de la CONCEPTION, Service d'Endocrinologie, Diabète et Maladies Métaboliques
city: Lübeck
country: Germany
facility: Med Clinic I - University of Lueback
city: Haifa
country: Israel
facility: Bnail Zion Medical Center Institute of Endocrinology & Metabolism
city: Petah Tikva
country: Israel
facility: Institute of Endocrinology & Metabolism, Rabin Medical Center
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center, Endocrinology & Metabolism
city: Ancona
country: Italy
facility: Azienda Ospedaliera-Universitaria Ancona
city: Messina
country: Italy
facility: UOC di Endocrinologia, Dipartimento di Medicina Clinica e Sperimentale
city: Milan
country: Italy
facility: Istituto Auxologico Italiano
city: Naples
country: Italy
facility: University of Naples Federico II
city: Orbassano
country: Italy
facility: SCDU Medicina Interna I Università di Torino Dipartimento di Scienze Cliniche e Biologiche
city: Padova
country: Italy
facility: University of Padua
city: Roma
country: Italy
facility: Institute of Medical Pathology
city: Torino
country: Italy
facility: Azienda Ospedaliero - Universitaria Città della Salute e della Scienza di Torino
city: Verona
country: Italy
facility: Policlinico GB Rossi
city: Leiden
country: Netherlands
facility: Leiden University, Leiden University Medical Center, Dept. of Endocrinology
city: Rotterdam
country: Netherlands
facility: Erasmus MC, Dpt. Of Internal Medicine, Division of Endocrinology
city: Lublin
country: Poland
facility: Terpa Sp.z.o.o
city: Poznań
country: Poland
facility: Szpital Kliniczny im. Heliodora Swiecickiego
city: Warszawa
country: Poland
facility: Outpatient Clinic: Reuma Centrum
city: Wroclaw
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1
city: Łódź
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Alzira
country: Spain
facility: Hospital Universidad De La Ribera
state: Valencia
city: Barcelona
country: Spain
facility: Endocrinologia, Hospital Sant Pau,Universitat Autònoma de Barcelona
city: Cordoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Istanbul
country: Turkey
facility: Bezmi Alem Vakıf Üniversitesi Endokrinoloji Bölümü Adnan
city: Istanbul
country: Turkey
facility: Istanbul University Medical Faculty
Study officials:
affiliation: Cortendo AB
name: Fredric J Cohen, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.