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

• ClinicalTrials.gov Identifier: NCT03277690
• Recruitment Status: Completed
• First Posted: September 11, 2017
• Results First Posted: November 8, 2022
• Last Update Posted: November 8, 2022
• Sponsor: Cortendo AB
• Information provided by (Responsible Party): Cortendo AB

Tracking Information

• First Submitted Date: September 7, 2017
• First Posted Date: September 11, 2017
• Results First Submitted Date: April 15, 2022
• Results First Posted Date: November 8, 2022
• Last Update Posted Date: November 8, 2022
• Actual Study Start Date: September 26, 2017
• Actual Primary Completion Date: June 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 15, 2022)

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. [ Time Frame: max. 9.5 weeks ]

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.

Original Primary Outcome Measures (submitted: September 7, 2017)

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. [ Time Frame: max. 9.5 weeks ]

Urinary free cortisol (UFC) level measurement

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Endogenous Cushing's Syndrome

Intervention

• Drug: Levoketoconazole

  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.

  Other Name: COR-003
• Drug: Placebo

  During the double-blind Withdrawal Phase, patients will receive placebo tablets.

  During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.

Study Arms

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 13, 2022): 84
• Original Estimated Enrollment (submitted: September 7, 2017): 35
• Actual Study Completion Date: August 31, 2020
• Actual Primary Completion Date: June 30, 2020 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Denmark, France, Greece, Hungary, Israel, Italy, Netherlands, Poland, Romania, Spain, United States

Administrative Information

• NCT Number: NCT03277690
• Other Study ID Numbers: COR-2017-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Cortendo AB
• Original Responsible Party: Same as current
• Current Study Sponsor: Cortendo AB
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Xavier Valencia, MD; Cortendo AB

• PRS Account: Cortendo AB
• Verification Date: October 2022