CompletedNCT03277690Updated Nov 8, 2022Results posted

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

A Phase 3 interventional study of Levoketoconazole and Placebo in Endogenous Cushing's Syndrome, sponsored by Cortendo AB. Completed at 45 sites in 12 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-11-08.

Sponsored by Cortendo AB · Phase 3, Interventional, and Treatment

Phase: Phase 3
Study type: Interventional
Enrollment: 84
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study 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.

Read the 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.

Conditions studied

Endogenous Cushing's Syndrome

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Keywords

Cushing Syndrome, Adrenocortical Hyperfunction

In context

Cushing Syndrome

130 studies on the registry are indexed under Cushing Syndrome; 40 are open to participants now.

This study's enrollment of 84 is above the median of 50 across 61 interventional studies indexed under Cushing Syndrome.

Browse Cushing Syndrome studies →

Lead sponsor

Cortendo AB is the lead sponsor of 6 studies on the registry; none are open to participants now.

Of its 6 completed or terminated interventional studies of FDA-regulated products, 3 (50%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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

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 design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 84 participants (actual)

Study arms

Experimental
Levoketoconazole
Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo
Drug: Levoketoconazole
Placebo comparator
Placebo
Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole
Drug: Placebo

Interventions

DrugLevoketoconazole
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.
Also known as: COR-003
DrugPlacebo
During the double-blind Withdrawal Phase, patients will receive placebo tablets. During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.

What researchers measure

Primary outcomes

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.
Time frame: max. 9.5 weeks

Results

Posted Nov 8, 2022

Participant flow

Dose Titration and Maintenance

Participant flow — Dose Titration and Maintenance
Milestone	Levoketoconazole	Placebo
Started	79	0
Completed	39	0
Not completed	40	0
Withdrew: Protocol violation	3	0
Withdrew: Physician decision	1	0
Withdrew: Sponsor decision - randomization closed	4	0
Withdrew: Lack of efficacy	9	0
Withdrew: Adverse event	15	0
Withdrew: Withdrawal by subject	8	0

Randomized Withdrawal

Participant flow — Randomized Withdrawal
Milestone	Levoketoconazole	Placebo
Started	22	22
Subjects which were previous levoketoconazole study completers	1	4
Subjects that are levoketoconazole treatment naïve subjects	21	18
Completed	21	22
Not completed	1	0
Withdrew: Withdrawal by subject	1	0

Restoration

Participant flow — Restoration
Milestone	Levoketoconazole	Placebo
Started	21	22
Subjects which were previous levoketoconazole study completers	1	4
Subjects that are levoketoconazole treatment naïve subjects	20	18
Completed	21	22
Not completed	0	0

Outcome measures

PrimaryNumber 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.

Time frame:: max. 9.5 weeks
Reported as:: Count of participants · Participants

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.
Participants	Levoketoconazole	Placebo
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.	9	21

Adverse events

Collected over The intent to treat (ITT) population adverse events (AEs) are reported for the length of time the subject was in the randomized withdrawal (RW) phase, up to 9.5 weeks. The safety population AEs are reported for the full study length from informed consent to end of study, up to approximately 51 weeks.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Levoketoconazole-ITT RW Phase	0/22 (0%)	1/22 (4.5%)	11/22 (50%)
Placebo- ITT RW Phase	0/22 (0%)	0/22 (0%)	10/22 (45.5%)
Safety Population	0/84 (0%)	13/84 (15.5%)	73/84 (86.9%)

Most frequent serious events

Showing 10 of 16

Most frequent serious events
Event	Levoketoconazole-ITT RW Phase	Placebo- ITT RW Phase	Safety Population
HypokalemiaMetabolism and nutrition disorders	1/22	0/22	3/84
Abdominal painGastrointestinal disorders	0/22	0/22	2/84
Liver disorderHepatobiliary disorders	0/22	0/22	2/84
Limb InjuryInjury, poisoning and procedural complications	0/22	0/22	1/84
Hepatic enzyme increasedInvestigations	0/22	0/22	1/84
Myocardial infarctionCardiac disorders	0/22	0/22	1/84
EpistaxisRespiratory, thoracic and mediastinal disorders	0/22	0/22	1/84
FatigueGeneral disorders	0/22	0/22	1/84
NauseaGastrointestinal disorders	0/22	0/22	1/84
Pancreatitis chronicGastrointestinal disorders	0/22	0/22	1/84

Most frequent other events

Showing 10 of 61

Most frequent other events
Event	Levoketoconazole-ITT RW Phase	Placebo- ITT RW Phase	Safety Population
NauseaGastrointestinal disorders	2/22	1/22	24/84
HypokalaemiaMetabolism and nutrition disorders	1/22	0/22	21/84
HypertensionVascular disorders	3/22	1/22	20/84
HeadacheNervous system disorders	2/22	2/22	19/84
DiarrhoeaGastrointestinal disorders	1/22	0/22	12/84
Electrocardiogram QT prolongedInvestigations	0/22	0/22	12/84
DizzinessNervous system disorders	0/22	2/22	11/84
FatigueGeneral disorders	2/22	1/22	10/84
Decreased appetiteMetabolism and nutrition disorders	1/22	1/22	10/84
VomitingGastrointestinal disorders	1/22	0/22	9/84

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Levoketoconazole	Placebo	Total
Mean	45.0 ± 11.97	43.6 ± 10.96	44.3 ± 11.36

Sex: Female, Male
Sex: Female, Male(Participants)	Levoketoconazole	Placebo	Total
Female	15	19	34
Male	7	3	10

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Levoketoconazole	Placebo	Total
Hispanic or Latino	2	0	2
Not Hispanic or Latino	20	22	42
Unknown or Not Reported	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Levoketoconazole	Placebo	Total
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	3	0	3
White	18	22	40
More than one race	0	0	0
Unknown or Not Reported	1	0	1

Region of Enrollment
Region of Enrollment(participants)	Levoketoconazole	Placebo	Total
Greece	4	0	4
Netherlands	0	1	1
Romania	1	3	4
Hungary	1	1	2
United States	3	5	8
Poland	1	1	2
Italy	3	4	7
Israel	1	3	4
Bulgaria	4	4	8
France	2	0	2
Spain	2	0	2

Receiving Anti-hypertensive Medication at Baseline
Receiving Anti-hypertensive Medication at Baseline(Participants)	Levoketoconazole	Placebo	Total
Yes	16	14	30
No	6	8	14

Receiving Anti-diabetic Medication at Baseline
Receiving Anti-diabetic Medication at Baseline(Participants)	Levoketoconazole	Placebo	Total
Yes	8	6	14
No	14	16	30

Anatomical etiology of endogenous Cushing's syndrome
Anatomical etiology of endogenous Cushing's syndrome(Participants)	Levoketoconazole	Placebo	Total
Cushing's Disease	18	20	38
Ectopic ACTH Secretion	0	0	0
Adrenal-Dependent	3	1	4
Unknown	1	1	2

1 further baseline measures are reported on the registry.

Study locations

45 sites

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

References and documents

Study documents

Study protocol · Sep 23, 2019
Statistical analysis plan · Aug 13, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Timeline

Tracking since Sep 25, 2026

ElapsedEstimatedEstimated, not yet reached

Ran from Sep 2017 to primary completion in Jun 2020, 33 months.

Results were first posted in Nov 2022, 2 years 4 months after primary completion. A results delay was requested in Mar 2021.

How these figures are worked out, and which studies are left out of them.

Registered: Sep 7, 2017
First posted: Sep 11, 2017
StartActual: Sep 26, 2017
Primary completionActual: Jun 30, 2020
CompletionActual: Aug 31, 2020
Results delay requested: Mar 12, 2021
Results first posted: Nov 8, 2022
Last update: Nov 8, 2022

What these dates mean

Start.: When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.: When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.: When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.: Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.

No changes since tracking began. The registry record was last updated on Nov 8, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03277690
Lead sponsor: Cortendo AB
Responsible party: Sponsor
First posted: Sep 11, 2017
Start date: Sep 26, 2017
Primary completion: Jun 30, 2020
Completion: Aug 31, 2020
Results posted: Nov 8, 2022
Last update: Nov 8, 2022

Study contacts

Xavier Valencia, MD

study director · Cortendo AB

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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