Cushing Disease, Cushing Syndrome
Conditions
Brief summary
This is a long-term, open-label extension study of levoketoconazole in participants with endogenous Cushing's Syndrome.
Detailed description
This is a long-term, open-label extension (OLE) study of levoketoconazole in participants with endogenous Cushing's Syndrome (CS) who have completed one or both parent studies or otherwise potentially qualify for this study, as defined in the eligibility criteria.
Interventions
DRUGLevoketoconazole
Levoketoconazole up to 1200 mg daily
Sponsors
Cortendo AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-Label Extension Study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Completed the Extended Evaluation Phase of Study COR-2012-01 (i.e. M12) 2. Completed the Restoration Phase of Study COR-2017-01 (i.e. RES2) NOTE: Participants meeting criteria 1 or 2 above who have had a break in therapy may be eligible only after discussion with the Medical Monitor. If eligible, such participants may require re-establishment of the Therapeutic Dose via titration. All participants who have had a break in therapy should be discussed with the Medical Monitor to determine the starting dose of levoketoconazole. Prior to resuming treatment with levoketoconazole, other therapies for Cushing's Syndrome must undergo an appropriate washout period, with minimum durations as follows: * Ketoconazole or metyrapone: 2 weeks; * Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks); * Octreotide acetate LAR, lanreotide Autogel, pasireotide LAR: 12 weeks; * Lanreotide SR: 8 weeks; * Octreotide acetate (immediate release) or short-acting pasireotide: 1 week; * Mifepristone (RU 486, KORLYM): 4 weeks; * Megestrol acetate or medroxyprogesterone acetate (and selected other synthetic progestins): 6 weeks. 3. Currently in a named patient program or other Expanded Access Program receiving levoketoconazole 4. Were levoketoconazole-naïve prior to entry and received early rescue therapy with open-label levoketoconazole in Study COR-2017-01. 5. Achieved a clinically meaningful partial response (with reduction of UFC) in Study COR-2017-01 at dose level 7 or at a maximally tolerated dose of levoketoconazole but did not meet the randomization criteria for Study COR-2017-01 at the end of the Dose Titration and Maintenance Phase when randomization was open. 6. Were levoketoconazole-naïve prior to entry and were enrolled in Study COR-2017-01 in the Dose Titration and Maintenance Phase when randomization was closed. (NOTE: Such subjects must receive at least 1 dose of levoketoconazole before transitioning to this study.) Key
Exclusion criteria
* Discontinued levoketoconazole while participating in Study COR-2012-01 or Study COR-2017-01 or a named patient program or other Expanded Access program, due to safety or tolerability concerns or lack of efficacy. * Scheduled for surgery for treatment of CS or received surgery for treatment of CS within the 6 weeks prior to Screening. * Treated with mitotane within 6 months prior to 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | From parent study Baseline to final study visit or up to a maximum of 3 years, whichever comes first. | Proportions of participants with mUFC: 1) Less or equal to the ULN of the reference range, 2) Above the ULN to 1.5x the ULN, and 3) Above 1.5x the ULN. |
Countries
Bulgaria, France, Greece, Hungary, Israel, Italy, Netherlands, Poland, Romania, Spain, United States
Participant flow
Recruitment details
Prior to enrolling, participants were required to meet all eligibility criteria including specifications with respect to participation and/or completion of participation in COR-2012-01 and/or COR-2017-01.
Pre-assignment details
There were 52 potential participants screened for participation in COR-2017-OLE; 51 were eligible for participation and 1 was not eligible for participation, as they failed to achieve a therapeutic dose in COR-2017-01.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants who received at least 1 dose of levoketoconazole in COR-2017-OLE. | 51 |
| Total | 51 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous All Participants | 44.1 years STANDARD_DEVIATION 11.23 |
| Age, Continuous Completers | 48.3 years STANDARD_DEVIATION 12.37 |
| BMI at COR-2017-OLE Baseline All Participants | 29.57 kg/m^2 STANDARD_DEVIATION 7.064 |
| BMI at COR-2017-OLE Baseline Completers | 28.38 kg/m^2 STANDARD_DEVIATION 5.962 |
| Ethnicity (NIH/OMB) All Participants Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) All Participants Not Hispanic or Latino | 47 Participants |
| Ethnicity (NIH/OMB) All Participants Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Completers Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Completers Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Completers Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) All Participants American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) All Participants Asian | 0 Participants |
| Race (NIH/OMB) All Participants Black or African American | 3 Participants |
| Race (NIH/OMB) All Participants More than one race | 0 Participants |
| Race (NIH/OMB) All Participants Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) All Participants Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) All Participants White | 46 Participants |
| Race (NIH/OMB) Completers American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Completers Asian | 0 Participants |
| Race (NIH/OMB) Completers Black or African American | 1 Participants |
| Race (NIH/OMB) Completers More than one race | 0 Participants |
| Race (NIH/OMB) Completers Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Completers Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Completers White | 23 Participants |
| Receiving Anti-diabetic Medication at COR-2017-OLE Baseline All Participants | 16 Participants |
| Receiving Anti-diabetic Medication at COR-2017-OLE Baseline Completers | 8 Participants |
| Receiving Anti-Hypertensive Medication at COR-2017-OLE Baseline All Participants | 33 Participants |
| Receiving Anti-Hypertensive Medication at COR-2017-OLE Baseline Completers | 17 Participants |
| Receiving Cholesterol-Reducing Medication at COR-2017-OLE Baseline All Participants | 8 Participants |
| Receiving Cholesterol-Reducing Medication at COR-2017-OLE Baseline Completers | 6 Participants |
| Region of Enrollment Bulgaria | 9 Participants |
| Region of Enrollment France | 2 Participants |
| Region of Enrollment Greece | 5 Participants |
| Region of Enrollment Hungary | 2 Participants |
| Region of Enrollment Israel | 6 Participants |
| Region of Enrollment Italy | 6 Participants |
| Region of Enrollment Netherlands | 4 Participants |
| Region of Enrollment Poland | 2 Participants |
| Region of Enrollment Romania | 3 Participants |
| Region of Enrollment Spain | 2 Participants |
| Region of Enrollment United States | 10 Participants |
| Sex: Female, Male All Participants Female | 40 Participants |
| Sex: Female, Male All Participants Male | 11 Participants |
| Sex: Female, Male Completers Female | 19 Participants |
| Sex: Female, Male Completers Male | 5 Participants |
| Weight at COR-2017-OLE Baseline All Participants | 80.15 kg STANDARD_DEVIATION 18.994 |
| Weight at COR-2017-OLE Baseline Completers | 76.58 kg STANDARD_DEVIATION 17.127 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 51 |
| other Total, other adverse events | 48 / 51 |
| serious Total, serious adverse events | 20 / 51 |
Outcome results
Primary
Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN)
Proportions of participants with mUFC: 1) Less or equal to the ULN of the reference range, 2) Above the ULN to 1.5x the ULN, and 3) Above 1.5x the ULN.
Time frame: From parent study Baseline to final study visit or up to a maximum of 3 years, whichever comes first.
Population: The number of participants at each timepoint is based on both the number of participants with evaluable mUFC data at each timepoint and the number of participants remaining in the study at each assessment timepoint.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 30 | Above 1.5x ULN | 6 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 36 | Less than or equal to ULN | 7 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 36 | Above ULN to 1.5x ULN | 3 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 36 | Above 1.5x ULN | 3 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Original Baseline | Less than or equal to ULN | 0 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Original Baseline | Above ULN to 1.5x ULN | 1 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Original Baseline | Above 1.5x ULN | 50 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | COR-2017-OLE Baseline | Less than or equal to ULN | 26 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | COR-2017-OLE Baseline | Above ULN to 1.5x ULN | 12 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | COR-2017-OLE Baseline | Above 1.5x ULN | 12 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 6 | Less than or equal to ULN | 20 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 6 | Above ULN to 1.5x ULN | 10 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 6 | Above 1.5x ULN | 10 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 12 | Less than or equal to ULN | 15 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 12 | Above ULN to 1.5x ULN | 11 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 12 | Above 1.5x ULN | 11 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 18 | Less than or equal to ULN | 16 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 18 | Above ULN to 1.5x ULN | 6 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 18 | Above 1.5x ULN | 6 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 24 | Less than or equal to ULN | 18 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 24 | Above ULN to 1.5x ULN | 5 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 24 | Above 1.5x ULN | 6 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 30 | Less than or equal to ULN | 15 Participants |
| All Participants | Proportions of Participants With Mean Urinary Free Cortisol (mUFC) Categorization Based on Upper Limit of Normal (ULN) | Month 30 | Above ULN to 1.5x ULN | 3 Participants |