Treatment for Endogenous Cushing's Syndrome

Endogenous Cushing's Syndrome Clinical Trial

— SONICS  

Official title:

An Open Label Study to Assess the Safety and Efficacy of COR-003 (Levoketoconazole) in the Treatment of Endogenous Cushing's Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01838551
• Other study ID #: COR-2012-01
• Status: Completed
• Phase: Phase 3
• Start date: August 2014
• Est. completion date: November 2018

Study information

• Verified date: March 2021
• Source: Cortendo AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 94
• Est. completion date: November 2018
• Est. primary completion date: April 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cushing Syndrome
• Endogenous Cushing's Syndrome
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Belgium	University Hospitals Leuven Department of Endocrinology	Leuven
Bulgaria	University Specialized Hospital for Active Treatment in Endocrinology (USHATE)	Sofia
Canada	St. Pauls Hospital/Vancouver General Hospital	Vancouver	British Columbia
Czechia	Vseobecna fakultni nemocnice v Praze - III. Interni klinika VFN a 1. LF UK	Praha
Denmark	Aarhus University Hospital	Aarhus
Denmark	Rigshospitalet,Copenhagen University Hospital	Copenhagen
France	Hôpital de la CONCEPTION, Service d'Endocrinologie, Diabète et Maladies Métaboliques	Marseille Cedex
Germany	Med Clinic I - University of Lueback	Lübeck
Israel	Bnail Zion Medical Center Institute of Endocrinology & Metabolism	Haifa
Israel	Institute of Endocrinology & Metabolism, Rabin Medical Center	Petah Tikva
Israel	Sourasky Medical Center, Endocrinology & Metabolism	Tel Aviv
Italy	Azienda Ospedaliera-Universitaria Ancona	Ancona
Italy	UOC di Endocrinologia, Dipartimento di Medicina Clinica e Sperimentale	Messina
Italy	Istituto Auxologico Italiano	Milan
Italy	University of Naples Federico II	Naples
Italy	SCDU Medicina Interna I Università di Torino Dipartimento di Scienze Cliniche e Biologiche	Orbassano
Italy	University of Padua	Padova
Italy	Institute of Medical Pathology	Roma
Italy	Azienda Ospedaliero - Universitaria Città della Salute e della Scienza di Torino	Torino
Italy	Policlinico GB Rossi	Verona
Netherlands	Leiden University, Leiden University Medical Center, Dept. of Endocrinology	Leiden
Netherlands	Erasmus MC, Dpt. Of Internal Medicine, Division of Endocrinology	Rotterdam
Poland	Instytut Centrum Zdrowia Matki Polki	Lódz
Poland	Terpa Sp.z.o.o	Lublin
Poland	Szpital Kliniczny im. Heliodora Swiecickiego	Poznan
Poland	Outpatient Clinic: Reuma Centrum	Warszawa
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1	Wroclaw
Serbia	Clinical Center of Serbia	Belgrade
Spain	Hospital Universidad De La Ribera	Alzira	Valencia
Spain	Endocrinologia, Hospital Sant Pau,Universitat Autònoma de Barcelona	Barcelona
Spain	Hospital Universitario Reina Sofía	Cordoba
Turkey	Bezmi Alem Vakif Üniversitesi Endokrinoloji Bölümü Adnan	Istanbul
Turkey	Istanbul University Medical Faculty	Istanbul
United States	University of New Mexico HSC	Albuquerque	New Mexico
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Johns Hopkins University	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	UCLA School of Medicine	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Allegheny Neuroendocrinology Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon

Sponsors (1)

Lead Sponsor	Collaborator
Cortendo AB

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Canada,  Czechia,  Denmark,  France,  Germany,  Israel,  Italy,  Netherlands,  Poland,  Serbia,  Spain,  Turkey, 

References & Publications (2)

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-l — View 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 Cus — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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