Endogenous Cushing's Syndrome
Conditions
Keywords
Cushing Syndrome, Adrenocortical Hyperfunction
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.
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.
DRUGPlacebo
During the double-blind Withdrawal Phase, patients will receive placebo tablets. During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.
Sponsors
Cortendo AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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:
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
Countries
Bulgaria, Denmark, France, Greece, Hungary, Israel, Italy, Netherlands, Poland, Romania, Spain, United States
Participant flow
Pre-assignment details
Variable therapeutic response results in customized therapeutic doses (TD). The study design included an initial Titration-maintenance phase to identify a TD for each subject. It included a requirement for maintenance at TD for at least 4 weeks prior to entering the Randomized-withdrawal (RW) phase. Then a 1:1 RW to placebo was used to establish efficacy of the active therapy. 5 additional subjects began directly in RW after completing the parent study without requiring re-titration to TD.
Participants by arm
| Arm | Count |
|---|---|
| Levoketoconazole Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo
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. | 22 |
| Placebo Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole
Placebo: During the double-blind Withdrawal Phase, patients will receive placebo tablets.
During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole. | 22 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Dose Titration and Maintenance | Adverse Event | 15 | 0 |
| Dose Titration and Maintenance | Lack of Efficacy | 9 | 0 |
| Dose Titration and Maintenance | Physician Decision | 1 | 0 |
| Dose Titration and Maintenance | Protocol Violation | 3 | 0 |
| Dose Titration and Maintenance | Sponsor decision - Randomization closed | 4 | 0 |
| Dose Titration and Maintenance | Withdrawal by Subject | 8 | 0 |
| Randomized Withdrawal | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Levoketoconazole |
|---|---|---|---|
| Age, Continuous | 43.6 years STANDARD_DEVIATION 10.96 | 44.3 years STANDARD_DEVIATION 11.36 | 45.0 years STANDARD_DEVIATION 11.97 |
| Anatomical etiology of endogenous Cushing's syndrome Adrenal-Dependent | 1 Participants | 4 Participants | 3 Participants |
| Anatomical etiology of endogenous Cushing's syndrome Cushing's Disease | 20 Participants | 38 Participants | 18 Participants |
| Anatomical etiology of endogenous Cushing's syndrome Ectopic ACTH Secretion | 0 Participants | 0 Participants | 0 Participants |
| Anatomical etiology of endogenous Cushing's syndrome Unknown | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 42 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mean Urinary Free Cortisol (mUFC) | 411.59 nmol/24 hours STANDARD_DEVIATION 436.176 | 575.14 nmol/24 hours STANDARD_DEVIATION 822.384 | 738.69 nmol/24 hours STANDARD_DEVIATION 1067.025 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 22 Participants | 40 Participants | 18 Participants |
| Receiving Anti-diabetic Medication at Baseline No | 16 Participants | 30 Participants | 14 Participants |
| Receiving Anti-diabetic Medication at Baseline Yes | 6 Participants | 14 Participants | 8 Participants |
| Receiving Anti-hypertensive Medication at Baseline No | 8 Participants | 14 Participants | 6 Participants |
| Receiving Anti-hypertensive Medication at Baseline Yes | 14 Participants | 30 Participants | 16 Participants |
| Region of Enrollment Bulgaria | 4 participants | 8 participants | 4 participants |
| Region of Enrollment France | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Greece | 0 participants | 4 participants | 4 participants |
| Region of Enrollment Hungary | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Israel | 3 participants | 4 participants | 1 participants |
| Region of Enrollment Italy | 4 participants | 7 participants | 3 participants |
| Region of Enrollment Netherlands | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Poland | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Romania | 3 participants | 4 participants | 1 participants |
| Region of Enrollment Spain | 0 participants | 2 participants | 2 participants |
| Region of Enrollment United States | 5 participants | 8 participants | 3 participants |
| Sex: Female, Male Female | 19 Participants | 34 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 10 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 | 0 / 84 |
| other Total, other adverse events | 11 / 22 | 10 / 22 | 73 / 84 |
| serious Total, serious adverse events | 1 / 22 | 0 / 22 | 13 / 84 |
Outcome results
Primary
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
Population: Intent to Treat (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levoketoconazole | 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 Participants |
| 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. | 21 Participants |