Back to resultsA Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing's Syndrome.
Primary Purpose
Endogenous Cushing's Syndrome
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Levoketoconazole
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Endogenous Cushing's Syndrome focused on measuring Cushing Syndrome, Adrenocortical Hyperfunction
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.
Sites / Locations
- Keck Medical Center University of Southern California HCII, Internal Medicine - Keck Hospital
- Cedars-Sinai Medical Center, Cedars-Sinai Pituitary Center
- UCLA School of Medicine, Medicine/Endocrinology Department
- The Center for Diabetes and Endocrine Care
- Emory University, Neurosurgery
- Northwestern University, Medicine - Endocrinology
- Johns Hopkins University, Endocrinology Department
- University of Michigan, Comprehensive Endocrine Research, Internal Medicine - MEND
- Washington University School of Medicine, Endocrinology
- Columbia University, College of P&S Medicine/Neuro-endocrine Unit
- Memorial Sloan Kettering Cancer Center, Endocrinology
- Oregon Health & Science University, Neurological Surgery
- Allegheny Neuroendocrinology Center, West Penn Allegheny Health System
- Alexandovska University Hospital, Clinic of Endocrinology & Metabolic Diseases
- University Multiprofile Hospital for Active Treatment "Aleksandrovska" EAD Clinic of Endocrinology and Metabolic Diseases
- University Specialized Hospital for Active Treatment in Endocrinology (USHATE) I Klinika
- Rigshospitalet, Copenhagen University Hospital, Endocrinology Department
- APHM Hôpital de la Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques
- Evangelismos Athens General Hospital, Department of Endocrinology
- General Hospital of Athens 'G. Gennimatas', Department of Endocrinology-Diabetes Centre
- General Hospital of Athens 'Laiko', "National and Kapodistrian University of Athens Medical School Pathophysiology - Endocrinology"
- University General Hospital of Ioannina, Department of Endocrinology
- Hippokration General Hospital, "Endocrinology and Diabetes Department
- Semmelweis Egyetem II. Belgyógyászati Klinika A.épület I.emelet ODM-labor
- Bnai Zion Medical Center, Institute of Endocrinology
- Rabin Medical Center- Beilinson Hospital, "Institute of Endocrinology & Metabolism, Beilinson Campus"
- Tel-Aviv Sourasky Medical Center Institute of Endocrinology, Metabolism and Hypertension
- Clinica di Endocrinologia e malattie del Metabolismo, Dipartimento Specialità Mediche
- University of Genova, Department of Internal Medicine & Medical Specialties (DiMI)
- AOU Policlinico G. Martino Sezione di Endocrinologia
- AOU Federico II, Sezione di Endocrinologia (Edificio 1, Secondo Piano)
- Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Endocrinology
- Policlinico Universitario Sant'Andrea, Scienze Mediche
- AOU Citta della Salure e della Scienza SC Endocrinologia, Diabetologia e Metabolismo
- Leiden University, Leiden University Medical Center, Department of Endocrinology
- Erasmus Medical Center, Department of Internal Medicine
- Maria Sklodowska-Curie Memorial Institute - Cancer Center Gliwice Branch, Nuclear Medicine and Endocrine Oncology Department
- Wojskowy Instytut Medyczny, Klinika Gastroenterologii, Endokrynologii I Chorob Wewnetrznych
- Instytut Centrum Zdrowia Matki Polki, Oddział Endokrynologii i Chorób Metabolicznych
- Spitalul Clinic Judetean Mures, Compartimentul de Endocrinologie
- Spitalul Clinic Judetean de Urgenta "Pius Brinzeu", Departamentul de Endocrinologie
- Institutul National de Endocrinologie C.I. Parhon, Sectia Clinica de Endocrinologie II, Patologia tiroidei de corelatie
- Spitalul Clinic Judetean de Urgenta Cluj-Napoca, Sectia Clinica Endocrinologie
- Hospital Universidad De La Ribera, Endocrinologia
- Hospital Universitario Ramón y Cajal, Endocrinology and Nutrition
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Levoketoconazole
Placebo
Arm Description
Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo
Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03277690
Brief Title
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
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
September 26, 2017 (Actual)
Primary Completion Date
June 30, 2020 (Actual)
Study Completion Date
August 31, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cortendo AB
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endogenous Cushing's Syndrome
Keywords
Cushing Syndrome, Adrenocortical Hyperfunction
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
84 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Levoketoconazole
Arm Type
Experimental
Arm Description
Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole
Intervention Type
Drug
Intervention Name(s)
Levoketoconazole
Other Intervention Name(s)
COR-003
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
During the double-blind Withdrawal Phase, patients will receive placebo tablets.
During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.
Primary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
max. 9.5 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xavier Valencia, MD
Organizational Affiliation
Cortendo AB
Official's Role
Study Director
Facility Information:
Facility Name
Keck Medical Center University of Southern California HCII, Internal Medicine - Keck Hospital
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Cedars-Sinai Medical Center, Cedars-Sinai Pituitary Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
UCLA School of Medicine, Medicine/Endocrinology Department
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
The Center for Diabetes and Endocrine Care
City
Fort Lauderdale
State/Province
Florida
ZIP/Postal Code
33312
Country
United States
Facility Name
Emory University, Neurosurgery
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Northwestern University, Medicine - Endocrinology
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Johns Hopkins University, Endocrinology Department
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
University of Michigan, Comprehensive Endocrine Research, Internal Medicine - MEND
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Washington University School of Medicine, Endocrinology
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University, College of P&S Medicine/Neuro-endocrine Unit
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center, Endocrinology
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Oregon Health & Science University, Neurological Surgery
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Allegheny Neuroendocrinology Center, West Penn Allegheny Health System
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15212
Country
United States
Facility Name
Alexandovska University Hospital, Clinic of Endocrinology & Metabolic Diseases
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
Facility Name
University Multiprofile Hospital for Active Treatment "Aleksandrovska" EAD Clinic of Endocrinology and Metabolic Diseases
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
Facility Name
University Specialized Hospital for Active Treatment in Endocrinology (USHATE) I Klinika
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
Facility Name
Rigshospitalet, Copenhagen University Hospital, Endocrinology Department
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Facility Name
APHM Hôpital de la Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques
City
Marseille
State/Province
Cedex 5
ZIP/Postal Code
13385
Country
France
Facility Name
Evangelismos Athens General Hospital, Department of Endocrinology
City
Athens
ZIP/Postal Code
10676
Country
Greece
Facility Name
General Hospital of Athens 'G. Gennimatas', Department of Endocrinology-Diabetes Centre
City
Athens
ZIP/Postal Code
11527
Country
Greece
Facility Name
General Hospital of Athens 'Laiko', "National and Kapodistrian University of Athens Medical School Pathophysiology - Endocrinology"
City
Athens
ZIP/Postal Code
11527
Country
Greece
Facility Name
University General Hospital of Ioannina, Department of Endocrinology
City
Ioánnina
ZIP/Postal Code
45110
Country
Greece
Facility Name
Hippokration General Hospital, "Endocrinology and Diabetes Department
City
Thessaloníki
ZIP/Postal Code
54642
Country
Greece
Facility Name
Semmelweis Egyetem II. Belgyógyászati Klinika A.épület I.emelet ODM-labor
City
Budapest
ZIP/Postal Code
1088
Country
Hungary
Facility Name
Bnai Zion Medical Center, Institute of Endocrinology
City
Haifa
ZIP/Postal Code
34802
Country
Israel
Facility Name
Rabin Medical Center- Beilinson Hospital, "Institute of Endocrinology & Metabolism, Beilinson Campus"
City
Petach Tikva
ZIP/Postal Code
49100
Country
Israel
Facility Name
Tel-Aviv Sourasky Medical Center Institute of Endocrinology, Metabolism and Hypertension
City
Tel Aviv
ZIP/Postal Code
642-3906
Country
Israel
Facility Name
Clinica di Endocrinologia e malattie del Metabolismo, Dipartimento Specialità Mediche
City
Ancona
ZIP/Postal Code
60126
Country
Italy
Facility Name
University of Genova, Department of Internal Medicine & Medical Specialties (DiMI)
City
Genova
ZIP/Postal Code
16132
Country
Italy
Facility Name
AOU Policlinico G. Martino Sezione di Endocrinologia
City
Messina
ZIP/Postal Code
98125
Country
Italy
Facility Name
AOU Federico II, Sezione di Endocrinologia (Edificio 1, Secondo Piano)
City
Napoli
ZIP/Postal Code
8031
Country
Italy
Facility Name
Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Endocrinology
City
Roma
ZIP/Postal Code
00168
Country
Italy
Facility Name
Policlinico Universitario Sant'Andrea, Scienze Mediche
City
Roma
ZIP/Postal Code
00189
Country
Italy
Facility Name
AOU Citta della Salure e della Scienza SC Endocrinologia, Diabetologia e Metabolismo
City
Torino
ZIP/Postal Code
10126
Country
Italy
Facility Name
Leiden University, Leiden University Medical Center, Department of Endocrinology
City
Leiden
ZIP/Postal Code
2333ZA
Country
Netherlands
Facility Name
Erasmus Medical Center, Department of Internal Medicine
City
Rotterdam
ZIP/Postal Code
3015CE
Country
Netherlands
Facility Name
Maria Sklodowska-Curie Memorial Institute - Cancer Center Gliwice Branch, Nuclear Medicine and Endocrine Oncology Department
City
Gliwice
ZIP/Postal Code
44-101
Country
Poland
Facility Name
Wojskowy Instytut Medyczny, Klinika Gastroenterologii, Endokrynologii I Chorob Wewnetrznych
City
Warsaw
ZIP/Postal Code
04-141
Country
Poland
Facility Name
Instytut Centrum Zdrowia Matki Polki, Oddział Endokrynologii i Chorób Metabolicznych
City
Łódź
ZIP/Postal Code
93-338
Country
Poland
Facility Name
Spitalul Clinic Judetean Mures, Compartimentul de Endocrinologie
City
Târgu-Mureş
State/Province
Mures
ZIP/Postal Code
540072
Country
Romania
Facility Name
Spitalul Clinic Judetean de Urgenta "Pius Brinzeu", Departamentul de Endocrinologie
City
Timişoara
State/Province
Timis
ZIP/Postal Code
300723
Country
Romania
Facility Name
Institutul National de Endocrinologie C.I. Parhon, Sectia Clinica de Endocrinologie II, Patologia tiroidei de corelatie
City
Bucuresti
ZIP/Postal Code
011863
Country
Romania
Facility Name
Spitalul Clinic Judetean de Urgenta Cluj-Napoca, Sectia Clinica Endocrinologie
City
Cluj-Napoca
ZIP/Postal Code
400349
Country
Romania
Facility Name
Hospital Universidad De La Ribera, Endocrinologia
City
Alzira
State/Province
Valencia
ZIP/Postal Code
46600
Country
Spain
Facility Name
Hospital Universitario Ramón y Cajal, Endocrinology and Nutrition
City
Madrid
ZIP/Postal Code
28034
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing's Syndrome.
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