Cushings Disease
Conditions
Keywords
LCI699, osilodrostat, Cushings Disease, open-label dose titration, randomized withdrawal
Brief summary
The study aimed to confirm long-term efficacy and safety of LCI699 for the treatment of patients with Cushing's disease. It was a pivotal trial which supported the registration of LCI699 for the treatment of patients with Cushing's disease in the US and the EU. This is a phase lll, multi-center, double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period which evaluated the safety and efficacy of LCI699 for the treatment of patients with Cushing's disease.
Detailed description
The primary objective compared the complete response rate at the end of the 8-week period of randomized withdrawal (Week 34) between patients randomized to continued osilodrostat therapy vs. placebo. The key secondary objective assessed the complete response rate at the end of individual dose titration and treatment with osilodrostat in the initial single-arm, open label period (Week 24). Eligible patients were randomized in a double-blinded fashion at Week 26 at a 1:1 ratio either to continue treatment with osilodrostat at the same dose or to matching placebo. Randomization was stratified by osilodrostat dose at Week 24 (≤ 5mg bid vs. \>5mg bid); and history of pituitary irradiation (yes/no). The study had four periods combined in the Core Period (Study Period 1 to 4) and an optional Extension Period. The optional Extension Period starting at Week 48. Study Period 1 consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients (Week 1 to Week 12). Dose adjustments were based on the mean of three 24-hour UFC (mUFC) values as measured by the central laboratory. During study Period 2 (Week 13 to Week 24), osilodrostat efficacy and safety were assessed at the therapeutic dose determined during study Period 1. Patients whose mUFC became elevated during this period had their osilodrostat dose increased further, if it was tolerated, up to 30 mg bid. Such patients were followed for long-term safety and efficacy and were not considered responders for the key secondary endpoint, hence were not randomized in Study Period 3. Study Period 3 was a double-blind, placebo-controlled randomized withdrawal (RW) Period (Week 26 to Week 34). In order to be eligible for randomization in study Period 3, patients had to have completed dose titration during study Period 1, and had to be classified as complete responders at Week 24 of study Period 2. Patients not eligible for randomization received open-label osilodrostat until the end of the Core Period (Week 48), unless there was a reason to discontinue from the study prematurely. During study Period 3, mUFC was measured at scheduled visits every 2 weeks. However, patients were also allowed to have unscheduled visits at any time during the RW if they reported symptoms of hypercortisolism or hypocortisolism. The dose of study drug remained unchanged for patients who maintained a normal mUFC and did not develop adverse events (AEs) related to study drug during RW. The Investigator could reduce or temporally withhold a dose of study drug for safety reasons at any time during the study, including the RW Period. During this study period, a patient was discontinued from the RW Period and declared a nonresponder, if the mUFC increased to \>1.5×ULN. After discontinuation from RW treatment, or at the end of the RW Period (Week 34), whichever came first, the patient resumed open-label osilodrostat at a dose selected by the Investigator. Patients who discontinued from the study during the RW Period were no longer in the study, and consequently were not permitted to receive open-label osilodrostat and could not move to study Period 4. Patients who discontinued from RW treatment due to lack of efficacy resumed open-label osilodrostat at the time of discontinuation, which could occur before Week 34. Patients who were not discontinued during RW resumed open-label osilodrostat at the end of RW (Week 34) and continued osilodrostat thereafter (study Period 4). The Novartis study team, the patient, the Investigator, and all other site staff remained blinded to treatment assignment from the time of randomization to the time of database lock at the end of the Core Period. Novartis Drug Supply Management department members were unblinded in order to prepare the study drug supplies. Study Period 4 was a single-arm, open-label therapy (end of Week 34 to Week 48). At the end of Week 34, all patients received open-label osilodrostat treatment. The Investigator had the discretion to select the dose during this period. Patients continued open-label therapy until Week 48. At Week 48, patients had the option to enter an Extension Period, or discontinue osilodrostat at Week 48 to conclude with an end of Core Period visit 4 weeks off study drug (at Week 52). Patients who continued to receive clinical benefit, as assessed by the study Investigator, and who wished to enter the Extension Period were re-consented at Week 48. Patients entered the Extension period without interruption of study drug or assessments. At the end of the study, patients who continued to benefit from treatment were offered to participate in a separate long-term safety follow-up study. The optional Extension Period ended after all patients completed Week 72 or discontinued early.
Interventions
DRUGosilodrostat
Osilodrostat comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat was 30 mg bid.
DRUGLCI699 matching placebo
Osilodrostat placebo comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat placebo was 30 mg bid.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
It is a double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed. 2. Male or female patients aged 18 - 75 years. 3. Patients must have confirmed Cushing's disease that is persistent or recurrent. 4. Patients with a history of prior pituitary surgery must be at least 30 days post-surgery to be eligible for inclusion in this study. 5. Patients that received glucocorticoid replacement therapy post-operatively must have discontinued such therapy for at least one week, or 5 half-lives, whichever is longer, prior to screening. 6. Patients with de novo Cushing's disease can be included only if they are not considered candidates for surgery. 7. Patients with a history of pituitary irradiation can be included, provided that at least 2 years (stereotactic radiosurgery) or 3 years (conventional radiation) have elapsed from the time of last radiation treatment to the time of enrollment into this study. 8. Patients are permitted to washout current drug therapy to meet these entry criteria if they have a known diagnosis of Cushing's disease.
Exclusion criteria
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half lives at the time of enrollment, whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations. 2. History of hypersensitivity to LCI699 or to drugs of similar chemical classes. 3. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. 4. Patients with risk factors for QTc prolongation or Torsade de Pointes. 5. Pregnant or nursing (lactating) women. 6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after completion of dosing. 7. Patients with compression of the optic chiasm due to a macroadenoma or patients at high risk of compression of the optic chiasm (tumor within 2 mm of optic chiasm). 8. Patients who have a known inherited syndrome as the cause for hormone over secretion. 9. Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH-independent (adrenal) Cushing's syndrome. 10. Patients who have undergone major surgery within 1 month prior to screening. 11. Hypertensive patients with uncontrolled blood pressure. 12. Diabetic patients with poorly controlled diabetes. 13. Patients who are not euthyroid as judged by the investigator. 14. Patients who have a history of: congestive heart failure, unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, acute MI less than one year prior to study entry, or clinically significant impairment in cardiovascular function. 15. Patients with moderate to severe renal impairment. 16. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with defined elevated ALT/ AST/ Bilirubin. 17. Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator or the sponsor's medical monitor. 18. Patients who have a history of alcohol or drug abuse in the 6 month period prior to study treatment. 19. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata | Week 34 (8 weeks) | To compare the complete response rate at the end of the 8-week period of randomized withdrawal between randomized patients.A primary efficacy responder is defined as a randomized patient who has mUFC ≤ ULN at Week 34 and who was neither discontinued (study or RW treatment) nor had osilodrostat dose increase above the level at Week 26 during the RW Period of the study. mUFC: mean urinary free cortisol; ULN: Upper Limit of Normal |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Actual Change From Baseline in mUFC | Weeks 12, 24, 48, 72, last available assessment | Actual change in mUFC from baseline. |
| Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint) | Week 24 | To assess the complete response rate at the end of individual dose-titration and treatment with LCI699 in the initial single-arm, open label period. A Key secondary efficacy responder is defined as a patient in FAS who has mUFC ≤ ULN at Week 24 and the dose of osilodrostat during Study Period 2 (Weeks 13-24) was not increased above the level established at the end of Study Period 1 (Week 12). Patients who had missing mUFC assessment at Week 24 will be counted as non-responders for the key secondary endpoint. |
| Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group | 8 weeks after randomization | Time-to-loss of control of mUFC during the RW Period, defined as the time (in days) from randomization to the first evidence of loss of control (defined as mUFC assessment \>1.5 ULN based on central laboratory result & at least 2 of the associated individual urine samples showing UFC \>1.5×ULN) within the RW period. A patient without evidence of loss of control was censored at the date of the last assessment with mUFC ≤ 1.5 ULN. If a patient discontinued randomized treatment without having a UFC assessment, they were censored at the date of randomization. The measure type (number) refers to an Event probability estimate 8 weeks after randomization. |
| Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Baseline, Weeks 48, 72, last available assessment | Actual change in fasting glucose from baseline. |
| Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Baseline, Weeks 48, 72, last available assessment | Actual change in glycosylated hemoglobin (HbA1c) from baseline. |
| Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Baseline, Weeks 48, 72, last available assessment | Actual change in Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride from baseline. |
| Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | Baseline, Weeks 48, 72, last available assessment | Actual change in sitting SBP & DBP from baseline. |
| Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Baseline, Weeks 48, 72, last available assessment | Actual change in weight from baseline. |
| Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Baseline, Weeks 48, 72, last available assessment | Actual change in BMI from baseline. |
| Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Baseline, Weeks 48, 72, last available assessment | Actual change in waist circumference from baseline. |
| Complete Response Rate (CRR) | Week 12, Week 24, Week 48, Week 72, last observed value | Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN |
| Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | Baseline, W48, W72, Last available assessment | BDI-II is a patient-reported instrument developed to measure the severity of depression in adults & adolescents aged 13 years & older. It is designed to be completed by the patient on paper & takes approximately 5 minutes to complete. The BDI-II consists of 21 items designed to assess the intensity of depression in clinical & normal patients in the preceding 2 weeks. Items are rated on a 4-point severity scale of 0 ('not at all') to 3 ('extreme' form of each symptom) with differing response options for each item. A global score ranging from 0 to 63 is calculated with a higher score representing a greater level of depression. The following scoring guidelines for interpretation of BDI-II have been suggested (Smarr, 2011): Minimal range =0-13, Mild depression =14-19, Moderate depression =20-28 and Severe depression = 29-63. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. A reduction from baseline in BDI-II is indicative of an improvement. |
| Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Baseline, W48, W72, Last available assessment | The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. It is cognitively undemanding, taking only a few minutes to complete. Instructions to respondents are included in the questionnaire. The EQ-5D-5L measures 5 items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 levels: no problems, slight problems, moderate problems, severe problems, & extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an unconscious health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement. |
| Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Baseline, W48, W72, Last available assessment | The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with on a scale of 0-100, with endpoints labeled 100 = 'the best health you can imagine' and 0 = 'the worst health you can imagine'. A single index value is analyzed for the VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement. |
| Change From Baseline in the Physical Features of Cushing's Disease by Photography | Week 48, Week 72, Last available assessment | Improvement from baseline to Weeks 48, 72 and End of Treatment (Extension period) in each of the following clinical signs of Cushing's disease by photography: facial rubor, hirsutism, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises). |
| Change From Baseline in Bone Mineral Density - All Participants | Baseline, Week 48, Last observed value (LOV) | Actual change from baseline to Week 48 and the LOV in bone mineral density as measured by DXA scan at the lumbar spine and total hip. An increase in bone mineral density is indicative of an improvement.. |
| Time-to-escape | From the first mUFC ≤ ULN to the first mUFC results > 1.5 x ULN with at least 2 individual UFC results > 1.5 x ULN | Escape was defined as the time (in days) from the first mUFC ≤ ULN to the first mUFC results \> 1.5 x ULN with at least 2 individual UFC results \> 1.5 x ULN the loss happened beyond 12-week dose titration period. Participants randomized to placebo were not included in the analysis. |
| LCI699 Exposures | from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose | To evaluate exposures of LCI699 in patients with Cushing's disease. Plasma concentrations (predose, 0.75 h, 1.5 h, and 4 h post-dose) of LCI699. These are the maximum number of PAS subjects analyzed for each incident dose. |
| Percentage of Participants With Complete Response Rate (CRR) | Week 12, Week 24, Week 48, Week 72, last available assessment | Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN. |
| Percentage of Participants With Partial Response Rate (PRR) | Week 12, Week 24, Week 48, Week 72, last available assessment | Partial response rate is defined as percentage of enrolled participants with ≥ 50% reduction from baseline in mUFC, but mUFC\>ULN) |
| Percentage of Participants With Overall Response Rate (ORR) | Week 12, Week 24, Week 48, Week 72, last available assessment | Overall response rate is defined as percentage of enrolled participants with mUFC ≤ ULN or at least 50% reduction from baseline. |
| Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Baseline, Week (W) 48, W72, Last available assessment | Cushing's Disease Health-Related Quality of Life Questionnaire was developed to evaluate quality of life in patients with Cushing's syndrome. It is comprised of 12 items that capture patient responses on 7 concepts: daily activities, healing & pain, mood & self-confidence, social concerns, physical appearance, memory & concern about the future. These items are measured on a 5- point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous 4 weeks. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Content reliability, sensitivity to change & psychometric properties have been validated in patients with Cushing's disease. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. Increases from baseline are indicative of an improvement. |
Countries
Argentina, Austria, Bulgaria, Canada, China, Colombia, France, Germany, India, Italy, Japan, Netherlands, Russia, South Korea, Spain, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
132 patients were planned, 137 were enrolled and 137 were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Osilodrostat (LCI699) Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period. | 36 |
| LCI699 Placebo Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period. | 35 |
| Non-randomized All participants in this group took open label osilodrostat, before and after randomization. | 66 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 | 22 |
| Overall Study | Death | 1 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 6 |
| Overall Study | Subject/Guardian decision | 5 | 3 | 6 |
| Overall Study | Unsatisfactory therapeutic effect | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 4 |
Baseline characteristics
| Characteristic | LCI699 Placebo | Non-randomized | Osilodrostat (LCI699) | Total |
|---|---|---|---|---|
| Age, Continuous | 42.0 years STANDARD_DEVIATION 13.47 | 39.0 years STANDARD_DEVIATION 13.38 | 44.3 years STANDARD_DEVIATION 11.27 | 41.2 years STANDARD_DEVIATION 12.98 |
| Race/Ethnicity, Customized Asian | 7 Participants | 25 Participants | 7 Participants | 39 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 23 Participants | 39 Participants | 27 Participants | 89 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Female | 22 Participants | 54 Participants | 30 Participants | 106 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 6 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 36 | 1 / 35 | 0 / 66 | 2 / 137 |
| other Total, other adverse events | 34 / 36 | 35 / 35 | 65 / 66 | 134 / 137 |
| serious Total, serious adverse events | 13 / 36 | 10 / 35 | 32 / 66 | 55 / 137 |
Outcome results
Primary
Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata
To compare the complete response rate at the end of the 8-week period of randomized withdrawal between randomized patients.A primary efficacy responder is defined as a randomized patient who has mUFC ≤ ULN at Week 34 and who was neither discontinued (study or RW treatment) nor had osilodrostat dose increase above the level at Week 26 during the RW Period of the study. mUFC: mean urinary free cortisol; ULN: Upper Limit of Normal
Time frame: Week 34 (8 weeks)
Population: Randomized analysis set (RAS): comprises all randomized patients who received at least one dose of randomized drug (osilodrostat or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osilodrostat (LCI699) | Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata | 86.1 Percentage of participants |
| LCI699 Placebo | Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata | 29.4 Percentage of participants |
p-value: <0.00195% CI: [3.73, 53.44]Cochran-Mantel-Haenszel
Secondary
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI)
Actual change in BMI from baseline.
Time frame: Baseline, Weeks 48, 72, last available assessment
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Baseline | 29.6 kg/m^2 | Standard Deviation 7.36 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Wk 48 | -1.3 kg/m^2 | Standard Deviation 2.22 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Wk 72 | -1.4 kg/m^2 | Standard Deviation 2.79 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Last avail. assessment | -1.2 kg/m^2 | Standard Deviation 3.34 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Last avail. assessment | -1.5 kg/m^2 | Standard Deviation 3.94 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Baseline | 30.9 kg/m^2 | Standard Deviation 8.38 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Wk 72 | -1.8 kg/m^2 | Standard Deviation 2.14 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Wk 48 | -1.5 kg/m^2 | Standard Deviation 2.12 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Last avail. assessment | -1.6 kg/m^2 | Standard Deviation 2.41 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Wk 48 | -1.5 kg/m^2 | Standard Deviation 2.17 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Wk 72 | -2.0 kg/m^2 | Standard Deviation 2.55 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) | Baseline | 30.4 kg/m^2 | Standard Deviation 7.74 |
Secondary
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride
Actual change in Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride from baseline.
Time frame: Baseline, Weeks 48, 72, last available assessment
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Wk 48 | -0.3 mmol/L | Standard Deviation 0.39 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: BL | 3.2 mmol/L | Standard Deviation 1.09 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: BL | 1.5 mmol/L | Standard Deviation 0.78 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: BL | 1.7 mmol/L | Standard Deviation 0.55 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Wk 48 | -0.3 mmol/L | Standard Deviation 0.75 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Wk 72 | 0.0 mmol/L | Standard Deviation 0.57 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Last avail asses | -0.1 mmol/L | Standard Deviation 0.98 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Wk 72 | -0.2 mmol/L | Standard Deviation 0.77 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Wk 48 | -0.7 mmol/L | Standard Deviation 0.87 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Last avail. assess | 0.0 mmol/L | Standard Deviation 0.64 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Wk 48 | -0.1 mmol/L | Standard Deviation 0.49 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Wk 72 | -0.4 mmol/L | Standard Deviation 0.96 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Wk 72 | -0.2 mmol/L | Standard Deviation 0.39 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Last avail assess | -0.2 mmol/L | Standard Deviation 0.4 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Last avail. assessment | -0.3 mmol/L | Standard Deviation 1.16 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: BL | 5.5 mmol/L | Standard Deviation 1.22 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Wk 72 | -0.3 mmol/L | Standard Deviation 0.75 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Wk 72 | -0.2 mmol/L | Standard Deviation 0.27 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: BL | 1.4 mmol/L | Standard Deviation 0.62 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: BL | 5.3 mmol/L | Standard Deviation 0.9 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Wk 48 | -0.4 mmol/L | Standard Deviation 0.89 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Last avail. assessment | -0.3 mmol/L | Standard Deviation 1.03 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: BL | 3.1 mmol/L | Standard Deviation 0.77 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Wk 48 | -0.2 mmol/L | Standard Deviation 0.74 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Wk 72 | -0.2 mmol/L | Standard Deviation 0.66 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Last avail asses | -0.2 mmol/L | Standard Deviation 0.88 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: BL | 1.5 mmol/L | Standard Deviation 0.36 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Wk 48 | -0.2 mmol/L | Standard Deviation 0.17 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Last avail assess | -0.1 mmol/L | Standard Deviation 0.27 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Wk 48 | 0.0 mmol/L | Standard Deviation 0.54 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Wk 72 | -0.1 mmol/L | Standard Deviation 0.67 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Last avail. assess | -0.1 mmol/L | Standard Deviation 0.75 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Last avail. assessment | -0.4 mmol/L | Standard Deviation 1.15 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Last avail. assess | 0.1 mmol/L | Standard Deviation 1.48 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Wk 48 | -0.3 mmol/L | Standard Deviation 0.28 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Wk 72 | -0.4 mmol/L | Standard Deviation 0.98 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Wk 72 | 0.0 mmol/L | Standard Deviation 0.6 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Last avail assess | -0.2 mmol/L | Standard Deviation 0.34 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: BL | 1.6 mmol/L | Standard Deviation 1.74 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: Wk 48 | -0.5 mmol/L | Standard Deviation 0.9 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: Wk 72 | -0.3 mmol/L | Standard Deviation 0.28 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Wk 72 | -0.1 mmol/L | Standard Deviation 0.86 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Wk 48 | -0.1 mmol/L | Standard Deviation 0.82 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Triglyceride: Wk 48 | 0.0 mmol/L | Standard Deviation 1.22 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: Last avail asses | -0.1 mmol/L | Standard Deviation 0.99 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | LDL Cholesterol: BL | 2.9 mmol/L | Standard Deviation 0.94 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | Cholesterol: BL | 5.1 mmol/L | Standard Deviation 1.24 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride | HDL Cholesterol: BL | 1.6 mmol/L | Standard Deviation 0.42 |
Secondary
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose
Actual change in fasting glucose from baseline.
Time frame: Baseline, Weeks 48, 72, last available assessment
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Wk 72 | -0.5 mg/dL | Standard Deviation 16.84 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Wk 48 | -7.9 mg/dL | Standard Deviation 32.24 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Last avail. assessment | -8.6 mg/dL | Standard Deviation 37.05 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Baseline | 102.7 mg/dL | Standard Deviation 35.23 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Wk 72 | -4.4 mg/dL | Standard Deviation 15.13 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Baseline | 90.5 mg/dL | Standard Deviation 18.53 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Wk 48 | -5.5 mg/dL | Standard Deviation 12.13 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Last avail. assessment | -0.6 mg/dL | Standard Deviation 21 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Wk 48 | -14.1 mg/dL | Standard Deviation 22.66 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Wk 72 | -10.8 mg/dL | Standard Deviation 24.02 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Baseline | 101.8 mg/dL | Standard Deviation 31 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose | Last avail. assessment | -15.6 mg/dL | Standard Deviation 26.62 |
Secondary
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C)
Actual change in glycosylated hemoglobin (HbA1c) from baseline.
Time frame: Baseline, Weeks 48, 72, last available assessment
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Wk 48 | -0.3 percentage | Standard Deviation 0.86 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Baseline | 6.1 percentage | Standard Deviation 0.98 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Wk 72 | -0.4 percentage | Standard Deviation 0.66 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Last avail. assessment | -0.3 percentage | Standard Deviation 0.78 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Last avail. assessment | -0.2 percentage | Standard Deviation 0.47 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Baseline | 5.8 percentage | Standard Deviation 0.93 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Wk 48 | -0.4 percentage | Standard Deviation 0.56 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Wk 72 | -0.4 percentage | Standard Deviation 0.47 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Baseline | 6.0 percentage | Standard Deviation 0.97 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Wk 72 | -0.4 percentage | Standard Deviation 0.64 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Last avail. assessment | -0.3 percentage | Standard Deviation 0.68 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) | Wk 48 | -0.4 percentage | Standard Deviation 0.65 |
Secondary
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP)
Actual change in sitting SBP & DBP from baseline.
Time frame: Baseline, Weeks 48, 72, last available assessment
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Wk 72 | -12.2 mmHg | Standard Deviation 15.9 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Last avail. assessment | -3.4 mmHg | Standard Deviation 11.79 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Baseline | 132.2 mmHg | Standard Deviation 15.44 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Wk 48 | -15.2 mmHg | Standard Deviation 17 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Last avail. assessment | -8.2 mmHg | Standard Deviation 15.25 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Baseline | 85.3 mmHg | Standard Deviation 11.38 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Wk 48 | -7.8 mmHg | Standard Deviation 11.63 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Wk 72 | -5.9 mmHg | Standard Deviation 11.17 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Wk 48 | -5.1 mmHg | Standard Deviation 9.66 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Wk 48 | -4.8 mmHg | Standard Deviation 12.28 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Last avail. assessment | -4.6 mmHg | Standard Deviation 15.2 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Baseline | 85.0 mmHg | Standard Deviation 10.03 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Wk 72 | -8.2 mmHg | Standard Deviation 19.41 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Last avail. assessment | -3.5 mmHg | Standard Deviation 11.5 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Wk 72 | -7.0 mmHg | Standard Deviation 10.33 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Baseline | 128.8 mmHg | Standard Deviation 11.93 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Baseline | 134.0 mmHg | Standard Deviation 16.34 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Last avail. assessment | -5.0 mmHg | Standard Deviation 10.45 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Wk 48 | -9.2 mmHg | Standard Deviation 15.48 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Wk 72 | -9.4 mmHg | Standard Deviation 19.08 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Wk 48 | -6.0 mmHg | Standard Deviation 11.79 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Baseline | 85.4 mmHg | Standard Deviation 10.53 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | SBP: Last avail. assessment | -10.8 mmHg | Standard Deviation 15.31 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) | DBP: Wk 72 | -4.8 mmHg | Standard Deviation 12.26 |
Secondary
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference
Actual change in waist circumference from baseline.
Time frame: Baseline, Weeks 48, 72, last available assessment
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Baseline | 100.5 cm | Standard Deviation 16.81 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Wk 48 | -5.1 cm | Standard Deviation 6.26 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Wk 72 | -5.1 cm | Standard Deviation 7.18 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Last avail. assessment | -4.7 cm | Standard Deviation 10.05 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Last avail. assessment | -5.2 cm | Standard Deviation 12.24 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Baseline | 103.7 cm | Standard Deviation 18.26 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Wk 72 | -6.1 cm | Standard Deviation 9.86 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Wk 48 | -4.2 cm | Standard Deviation 10.12 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Last avail. assessment | -6.2 cm | Standard Deviation 9.96 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Wk 48 | -4.7 cm | Standard Deviation 7.07 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Wk 72 | -7.4 cm | Standard Deviation 8.53 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference | Baseline | 105.0 cm | Standard Deviation 21.15 |
Secondary
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight
Actual change in weight from baseline.
Time frame: Baseline, Weeks 48, 72, last available assessment
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Baseline | 78.2 kg | Standard Deviation 19.02 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Wk 48 | -3.4 kg | Standard Deviation 5.64 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Wk 72 | -3.7 kg | Standard Deviation 6.93 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Last avail. assessment | -2.9 kg | Standard Deviation 8.28 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Last avail. assessment | -3.7 kg | Standard Deviation 11.13 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Baseline | 83.4 kg | Standard Deviation 24.73 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Wk 72 | -5.0 kg | Standard Deviation 6.03 |
| LCI699 Placebo | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Wk 48 | -3.9 kg | Standard Deviation 5.77 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Last avail. assessment | -4.2 kg | Standard Deviation 6.35 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Wk 48 | -4.0 kg | Standard Deviation 5.82 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Wk 72 | -5.6 kg | Standard Deviation 6.75 |
| Non-randomized | Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight | Baseline | 80.7 kg | Standard Deviation 23.06 |
Secondary
Actual Change From Baseline in mUFC
Actual change in mUFC from baseline.
Time frame: Weeks 12, 24, 48, 72, last available assessment
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in mUFC | Actual Baseline (BL) | 890.0 nmol/24h | Standard Deviation 1275.66 |
| Osilodrostat (LCI699) | Actual Change From Baseline in mUFC | Wk 12: Act. change from BL | -848.4 nmol/24h | Standard Deviation 1335.66 |
| Osilodrostat (LCI699) | Actual Change From Baseline in mUFC | Wk 24: Act. change from BL | -821.2 nmol/24h | Standard Deviation 1283.03 |
| Osilodrostat (LCI699) | Actual Change From Baseline in mUFC | Wk 48: Act. change from BL | -708.2 nmol/24h | Standard Deviation 983.14 |
| Osilodrostat (LCI699) | Actual Change From Baseline in mUFC | Wk 72: Act. change from BL | -680.7 nmol/24h | Standard Deviation 1003.63 |
| Osilodrostat (LCI699) | Actual Change From Baseline in mUFC | Last avail. assess.: Act. change from BL | -795.2 nmol/24h | Standard Deviation 1286.22 |
| LCI699 Placebo | Actual Change From Baseline in mUFC | Last avail. assess.: Act. change from BL | -387.3 nmol/24h | Standard Deviation 605.63 |
| LCI699 Placebo | Actual Change From Baseline in mUFC | Actual Baseline (BL) | 560.0 nmol/24h | Standard Deviation 548.84 |
| LCI699 Placebo | Actual Change From Baseline in mUFC | Wk 48: Act. change from BL | -477.1 nmol/24h | Standard Deviation 529.04 |
| LCI699 Placebo | Actual Change From Baseline in mUFC | Wk 72: Act. change from BL | -536.7 nmol/24h | Standard Deviation 585.78 |
| LCI699 Placebo | Actual Change From Baseline in mUFC | Wk 12: Act. change from BL | -510.3 nmol/24h | Standard Deviation 556.84 |
| LCI699 Placebo | Actual Change From Baseline in mUFC | Wk 24: Act. change from BL | -485.5 nmol/24h | Standard Deviation 558.99 |
| Non-randomized | Actual Change From Baseline in mUFC | Wk 12: Act. change from BL | -1021.3 nmol/24h | Standard Deviation 1825.55 |
| Non-randomized | Actual Change From Baseline in mUFC | Wk 24: Act. change from BL | -930.3 nmol/24h | Standard Deviation 1778.04 |
| Non-randomized | Actual Change From Baseline in mUFC | Last avail. assess.: Act. change from BL | -893.4 nmol/24h | Standard Deviation 1969.56 |
| Non-randomized | Actual Change From Baseline in mUFC | Wk 48: Act. change from BL | -1189.9 nmol/24h | Standard Deviation 2042.48 |
| Non-randomized | Actual Change From Baseline in mUFC | Actual Baseline (BL) | 1305.8 nmol/24h | Standard Deviation 2012.21 |
| Non-randomized | Actual Change From Baseline in mUFC | Wk 72: Act. change from BL | -826.7 nmol/24h | Standard Deviation 1684.92 |
Secondary
Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)
BDI-II is a patient-reported instrument developed to measure the severity of depression in adults & adolescents aged 13 years & older. It is designed to be completed by the patient on paper & takes approximately 5 minutes to complete. The BDI-II consists of 21 items designed to assess the intensity of depression in clinical & normal patients in the preceding 2 weeks. Items are rated on a 4-point severity scale of 0 ('not at all') to 3 ('extreme' form of each symptom) with differing response options for each item. A global score ranging from 0 to 63 is calculated with a higher score representing a greater level of depression. The following scoring guidelines for interpretation of BDI-II have been suggested (Smarr, 2011): Minimal range =0-13, Mild depression =14-19, Moderate depression =20-28 and Severe depression = 29-63. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. A reduction from baseline in BDI-II is indicative of an improvement.
Time frame: Baseline, W48, W72, Last available assessment
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | Baseline | 15.1 scores on a a scale | Standard Deviation 11.14 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | W48 | -4.8 scores on a a scale | Standard Deviation 9.84 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | W72 | -6.0 scores on a a scale | Standard Deviation 9.55 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | Last avail. assess. | -6.2 scores on a a scale | Standard Deviation 9.93 |
| LCI699 Placebo | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | Last avail. assess. | -5.0 scores on a a scale | Standard Deviation 9.49 |
| LCI699 Placebo | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | Baseline | 17.8 scores on a a scale | Standard Deviation 9.93 |
| LCI699 Placebo | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | W72 | -4.6 scores on a a scale | Standard Deviation 9.41 |
| LCI699 Placebo | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | W48 | -5.3 scores on a a scale | Standard Deviation 7.99 |
| Non-randomized | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | Last avail. assess. | -4.9 scores on a a scale | Standard Deviation 10.66 |
| Non-randomized | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | W48 | -7.0 scores on a a scale | Standard Deviation 10.17 |
| Non-randomized | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | W72 | -9.0 scores on a a scale | Standard Deviation 12.34 |
| Non-randomized | Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) | Baseline | 17.3 scores on a a scale | Standard Deviation 10.67 |
Secondary
Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score
Cushing's Disease Health-Related Quality of Life Questionnaire was developed to evaluate quality of life in patients with Cushing's syndrome. It is comprised of 12 items that capture patient responses on 7 concepts: daily activities, healing & pain, mood & self-confidence, social concerns, physical appearance, memory & concern about the future. These items are measured on a 5- point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous 4 weeks. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Content reliability, sensitivity to change & psychometric properties have been validated in patients with Cushing's disease. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. Increases from baseline are indicative of an improvement.
Time frame: Baseline, Week (W) 48, W72, Last available assessment
Population: FAS: Comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Week 48 | 16.1 scores on a scale | Standard Deviation 15.15 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Baseline | 44.4 scores on a scale | Standard Deviation 18.33 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Last available assess. | 16.1 scores on a scale | Standard Deviation 15.99 |
| Osilodrostat (LCI699) | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Week 72 | 15.8 scores on a scale | Standard Deviation 16.08 |
| LCI699 Placebo | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Baseline | 43.2 scores on a scale | Standard Deviation 22.45 |
| LCI699 Placebo | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Week 72 | 12.6 scores on a scale | Standard Deviation 20.68 |
| LCI699 Placebo | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Week 48 | 10.2 scores on a scale | Standard Deviation 16.57 |
| LCI699 Placebo | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Last available assess. | 11.8 scores on a scale | Standard Deviation 20.51 |
| Non-randomized | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Last available assess. | 12.9 scores on a scale | Standard Deviation 18.91 |
| Non-randomized | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Week 48 | 13.2 scores on a scale | Standard Deviation 17.79 |
| Non-randomized | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Week 72 | 16.3 scores on a scale | Standard Deviation 21.31 |
| Non-randomized | Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score | Baseline | 40.5 scores on a scale | Standard Deviation 17.61 |
Secondary
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index
The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. It is cognitively undemanding, taking only a few minutes to complete. Instructions to respondents are included in the questionnaire. The EQ-5D-5L measures 5 items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 levels: no problems, slight problems, moderate problems, severe problems, & extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an unconscious health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement.
Time frame: Baseline, W48, W72, Last available assessment
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Baseline | 0.7 Scores on a scale | Standard Deviation 0.24 |
| Osilodrostat (LCI699) | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Week 48 | 0.1 Scores on a scale | Standard Deviation 0.18 |
| Osilodrostat (LCI699) | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Week 72 | 0.1 Scores on a scale | Standard Deviation 0.18 |
| Osilodrostat (LCI699) | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Last avail. assess. | 0.1 Scores on a scale | Standard Deviation 0.22 |
| LCI699 Placebo | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Last avail. assess. | 0 Scores on a scale | Standard Deviation 0.28 |
| LCI699 Placebo | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Baseline | 0.7 Scores on a scale | Standard Deviation 0.24 |
| LCI699 Placebo | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Week 72 | 0.1 Scores on a scale | Standard Deviation 0.26 |
| LCI699 Placebo | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Week 48 | 0 Scores on a scale | Standard Deviation 0.25 |
| Non-randomized | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Last avail. assess. | 0.1 Scores on a scale | Standard Deviation 0.23 |
| Non-randomized | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Week 48 | 0.1 Scores on a scale | Standard Deviation 0.18 |
| Non-randomized | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Week 72 | 0.1 Scores on a scale | Standard Deviation 0.19 |
| Non-randomized | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index | Baseline | 0.7 Scores on a scale | Standard Deviation 0.28 |
Secondary
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS)
The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with on a scale of 0-100, with endpoints labeled 100 = 'the best health you can imagine' and 0 = 'the worst health you can imagine'. A single index value is analyzed for the VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.
Time frame: Baseline, W48, W72, Last available assessment
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Baseline | 61.3 Scores on a scale | Standard Deviation 18.97 |
| Osilodrostat (LCI699) | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Week 48 | 12.6 Scores on a scale | Standard Deviation 20.64 |
| Osilodrostat (LCI699) | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Week 72 | 11.2 Scores on a scale | Standard Deviation 18.98 |
| Osilodrostat (LCI699) | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Last avail. assess. | 12.1 Scores on a scale | Standard Deviation 19.71 |
| LCI699 Placebo | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Last avail. assess. | 6.4 Scores on a scale | Standard Deviation 18.65 |
| LCI699 Placebo | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Baseline | 64.2 Scores on a scale | Standard Deviation 16.37 |
| LCI699 Placebo | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Week 72 | 6.6 Scores on a scale | Standard Deviation 15.47 |
| LCI699 Placebo | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Week 48 | 6.9 Scores on a scale | Standard Deviation 12.56 |
| Non-randomized | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Last avail. assess. | 6.2 Scores on a scale | Standard Deviation 20.42 |
| Non-randomized | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Week 48 | 9.7 Scores on a scale | Standard Deviation 17.16 |
| Non-randomized | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Week 72 | 10.1 Scores on a scale | Standard Deviation 19.8 |
| Non-randomized | Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) | Baseline | 60.8 Scores on a scale | Standard Deviation 21.09 |
Secondary
Change From Baseline in Bone Mineral Density - All Participants
Actual change from baseline to Week 48 and the LOV in bone mineral density as measured by DXA scan at the lumbar spine and total hip. An increase in bone mineral density is indicative of an improvement..
Time frame: Baseline, Week 48, Last observed value (LOV)
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | Change From Baseline in Bone Mineral Density - All Participants | Baseline (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.2 |
| Osilodrostat (LCI699) | Change From Baseline in Bone Mineral Density - All Participants | W48 (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.19 |
| Osilodrostat (LCI699) | Change From Baseline in Bone Mineral Density - All Participants | LOV (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.2 |
| Osilodrostat (LCI699) | Change From Baseline in Bone Mineral Density - All Participants | Baseline (Total Hip) | 0.9 g/cm2 | Standard Error 0.18 |
| Osilodrostat (LCI699) | Change From Baseline in Bone Mineral Density - All Participants | W48 (Total Hip) | 0.9 g/cm2 | Standard Error 0.17 |
| Osilodrostat (LCI699) | Change From Baseline in Bone Mineral Density - All Participants | LOV (Total Hip) | 0.9 g/cm2 | Standard Error 0.17 |
| LCI699 Placebo | Change From Baseline in Bone Mineral Density - All Participants | LOV (Total Hip) | 0.8 g/cm2 | Standard Error 0.13 |
| LCI699 Placebo | Change From Baseline in Bone Mineral Density - All Participants | Baseline (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.17 |
| LCI699 Placebo | Change From Baseline in Bone Mineral Density - All Participants | Baseline (Total Hip) | 0.8 g/cm2 | Standard Error 0.15 |
| LCI699 Placebo | Change From Baseline in Bone Mineral Density - All Participants | W48 (Total Hip) | 0.8 g/cm2 | Standard Error 0.14 |
| LCI699 Placebo | Change From Baseline in Bone Mineral Density - All Participants | W48 (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.17 |
| LCI699 Placebo | Change From Baseline in Bone Mineral Density - All Participants | LOV (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.18 |
| Non-randomized | Change From Baseline in Bone Mineral Density - All Participants | W48 (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.19 |
| Non-randomized | Change From Baseline in Bone Mineral Density - All Participants | LOV (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.18 |
| Non-randomized | Change From Baseline in Bone Mineral Density - All Participants | LOV (Total Hip) | 0.9 g/cm2 | Standard Error 0.16 |
| Non-randomized | Change From Baseline in Bone Mineral Density - All Participants | Baseline (Total Hip) | 0.9 g/cm2 | Standard Error 0.16 |
| Non-randomized | Change From Baseline in Bone Mineral Density - All Participants | Baseline (L1-L4 Lumbar Spine) | 1.0 g/cm2 | Standard Error 0.18 |
| Non-randomized | Change From Baseline in Bone Mineral Density - All Participants | W48 (Total Hip) | 0.9 g/cm2 | Standard Error 0.16 |
Secondary
Change From Baseline in the Physical Features of Cushing's Disease by Photography
Improvement from baseline to Weeks 48, 72 and End of Treatment (Extension period) in each of the following clinical signs of Cushing's disease by photography: facial rubor, hirsutism, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises).
Time frame: Week 48, Week 72, Last available assessment
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Facial rubor | 48.3 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Facial rubor | 50.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | End of Trial (EOT):Facial rubor | 60.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Striae | 27.6 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Dorsal fat pad | 60.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Ecchymoses | 27.6 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72:Supraclavicular fat pad | 55.2 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Ecchymoses | 28.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Central obesity | 37.9 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Dorsal fat pad | 69.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Proximal muscle atrophy | 36.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Proximal muscle atrophy | 31.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Proximal muscle atrophy | 40.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Central obesity | 40.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Dorsal fat pad | 56.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Central obesity | 43.3 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48:Supraclavicular fat pad | 56.7 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT:Supraclavicular fat pad | 52.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Ecchymoses | 33.3 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Striae | 30.0 Percentage of participants |
| Osilodrostat (LCI699) | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Striae | 32.0 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Proximal muscle atrophy | 21.7 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Facial rubor | 46.7 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Striae | 23.3 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48:Supraclavicular fat pad | 43.3 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Dorsal fat pad | 40.0 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Proximal muscle atrophy | 26.7 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Central obesity | 30.0 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Ecchymoses | 26.7 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Facial rubor | 55.6 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Striae | 25.9 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72:Supraclavicular fat pad | 51.9 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Dorsal fat pad | 48.1 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Proximal muscle atrophy | 25.9 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Central obesity | 37.0 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Ecchymoses | 29.6 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | End of Trial (EOT):Facial rubor | 56.5 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Striae | 34.8 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT:Supraclavicular fat pad | 43.5 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Dorsal fat pad | 52.2 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Central obesity | 39.1 Percentage of participants |
| LCI699 Placebo | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Ecchymoses | 39.1 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Facial rubor | 53.3 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Striae | 40.5 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | End of Trial (EOT):Facial rubor | 53.8 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Ecchymoses | 43.2 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Ecchymoses | 38.5 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Striae | 30.8 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Central obesity | 51.4 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Central obesity | 38.5 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT:Supraclavicular fat pad | 42.3 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Proximal muscle atrophy | 45.9 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Facial rubor | 43.2 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Dorsal fat pad | 46.2 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Dorsal fat pad | 53.3 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48: Dorsal fat pad | 56.8 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Proximal muscle atrophy | 46.7 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72:Supraclavicular fat pad | 53.3 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W48:Supraclavicular fat pad | 54.1 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Central obesity | 43.3 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Striae | 36.7 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | EOT: Proximal muscle atrophy | 50.0 Percentage of participants |
| Non-randomized | Change From Baseline in the Physical Features of Cushing's Disease by Photography | W72: Ecchymoses | 36.7 Percentage of participants |
Secondary
Complete Response Rate (CRR)
Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN
Time frame: Week 12, Week 24, Week 48, Week 72, last observed value
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Osilodrostat (LCI699) | Complete Response Rate (CRR) | Week 72 | 82.9 Percentage of participants |
| Osilodrostat (LCI699) | Complete Response Rate (CRR) | Week 48 | 88.9 Percentage of participants |
| Osilodrostat (LCI699) | Complete Response Rate (CRR) | Last observed value | 69.4 Percentage of participants |
| Osilodrostat (LCI699) | Complete Response Rate (CRR) | Week 12 | 86.1 Percentage of participants |
| Osilodrostat (LCI699) | Complete Response Rate (CRR) | Week 24 | 100.0 Percentage of participants |
| LCI699 Placebo | Complete Response Rate (CRR) | Week 24 | 97.1 Percentage of participants |
| LCI699 Placebo | Complete Response Rate (CRR) | Week 12 | 91.4 Percentage of participants |
| LCI699 Placebo | Complete Response Rate (CRR) | Week 48 | 77.1 Percentage of participants |
| LCI699 Placebo | Complete Response Rate (CRR) | Last observed value | 74.3 Percentage of participants |
| LCI699 Placebo | Complete Response Rate (CRR) | Week 72 | 83.3 Percentage of participants |
| Non-randomized | Complete Response Rate (CRR) | Last observed value | 53.0 Percentage of participants |
| Non-randomized | Complete Response Rate (CRR) | Week 48 | 48.5 Percentage of participants |
| Non-randomized | Complete Response Rate (CRR) | Week 12 | 53.0 Percentage of participants |
| Non-randomized | Complete Response Rate (CRR) | Week 24 | 34.8 Percentage of participants |
| Non-randomized | Complete Response Rate (CRR) | Week 72 | 78.0 Percentage of participants |
Secondary
LCI699 Exposures
To evaluate exposures of LCI699 in patients with Cushing's disease. Plasma concentrations (predose, 0.75 h, 1.5 h, and 4 h post-dose) of LCI699. These are the maximum number of PAS subjects analyzed for each incident dose.
Time frame: from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose
Population: Pharmacokinetics analysis set (PAS) consists of all enrolled patients who receive at least one dose of osilodrostat and have at least one evaluable post-dosing PK assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 6: Predose | 2.037 ng/ml | Geometric Coefficient of Variation 63.5 |
| Osilodrostat (LCI699) | LCI699 Exposures | Week (Wk) 2: Predose | 1.904 ng/ml | Geometric Coefficient of Variation 110.4 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 2: 0.75h | 1.907 ng/ml | Geometric Coefficient of Variation 132.5 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 2: 1.5h | 5.1 ng/ml | Geometric Coefficient of Variation 62.7 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 2: 4h | 5.818 ng/ml | Geometric Coefficient of Variation 66.3 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 4: Predose | 2.104 ng/ml | Geometric Coefficient of Variation 108 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 4: 0.75h | 0.859 ng/ml | Geometric Coefficient of Variation 254.3 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 4: 1.5h | 8.737 ng/ml | Geometric Coefficient of Variation 3.6 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 4: 4h | 8.930 ng/ml | — |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 6: 0.75h | 3.110 ng/ml | — |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 6: 4h | 8.380 ng/ml | — |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 8: Predose | 2.198 ng/ml | Geometric Coefficient of Variation 108.9 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 8: 1.5h | 10.8 ng/ml | — |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 8: 4h | 6.65 ng/ml | — |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 10: Predose | 1.862 ng/ml | Geometric Coefficient of Variation 128.9 |
| Osilodrostat (LCI699) | LCI699 Exposures | Wk 10: 1.5h | 12.1 ng/ml | — |
| LCI699 Placebo | LCI699 Exposures | Wk 10: 1.5h | 18.3 ng/ml | — |
| LCI699 Placebo | LCI699 Exposures | Wk 10: 4h | 15.8 ng/ml | — |
| LCI699 Placebo | LCI699 Exposures | Wk 8: 1.5h | 20.4 ng/ml | — |
| LCI699 Placebo | LCI699 Exposures | Wk 4: Predose | 2.898 ng/ml | Geometric Coefficient of Variation 109.1 |
| LCI699 Placebo | LCI699 Exposures | Wk 6: Predose | 2.392 ng/ml | Geometric Coefficient of Variation 285.6 |
| LCI699 Placebo | LCI699 Exposures | Wk 6: 4h | 18.6 ng/ml | — |
| LCI699 Placebo | LCI699 Exposures | Wk 10: Predose | 3.007 ng/ml | Geometric Coefficient of Variation 64.8 |
| LCI699 Placebo | LCI699 Exposures | Wk 6: 1.5h | 22.4 ng/ml | — |
| LCI699 Placebo | LCI699 Exposures | Wk 10: 0.75h | 6.7 ng/ml | — |
| LCI699 Placebo | LCI699 Exposures | Wk 8: Predose | 4.061 ng/ml | Geometric Coefficient of Variation 67.4 |
| Non-randomized | LCI699 Exposures | Wk 6: Predose | 5.087 ng/ml | Geometric Coefficient of Variation 122.9 |
| Non-randomized | LCI699 Exposures | Wk 6: 0.75h | 5.223 ng/ml | Geometric Coefficient of Variation 229.4 |
| Non-randomized | LCI699 Exposures | Wk 6: 1.5h | 21.4 ng/ml | — |
| Non-randomized | LCI699 Exposures | Wk 6: 4h | 18.373 ng/ml | Geometric Coefficient of Variation 36.5 |
| Non-randomized | LCI699 Exposures | Wk 10: 1.5h | 34.2 ng/ml | — |
| Non-randomized | LCI699 Exposures | Wk 8: Predose | 4.487 ng/ml | Geometric Coefficient of Variation 106.9 |
| Non-randomized | LCI699 Exposures | Wk 10: 4h | 27.2 ng/ml | — |
| Non-randomized | LCI699 Exposures | Wk 10: Predose | 4.704 ng/ml | Geometric Coefficient of Variation 106.8 |
| Non-randomized | LCI699 Exposures | Wk 4: Predose | 3.584 ng/ml | Geometric Coefficient of Variation 126.3 |
| Non-randomized | LCI699 Exposures | Wk 4: 0.75h | 7.091 ng/ml | Geometric Coefficient of Variation 137.8 |
| Non-randomized | LCI699 Exposures | Wk 4: 1.5h | 24.2 ng/ml | — |
| Non-randomized | LCI699 Exposures | Wk 4: 4h | 15.985 ng/ml | Geometric Coefficient of Variation 48.3 |
| Osilodrostat (LCI699) 7 mg | LCI699 Exposures | Wk 10: Predose | 5.451 ng/ml | Geometric Coefficient of Variation 93.1 |
| Osilodrostat (LCI699) 7 mg | LCI699 Exposures | Wk 10: 0.75h | 17.1 ng/ml | — |
| Osilodrostat (LCI699) 7 mg | LCI699 Exposures | Wk 10: 4h | 35.5 ng/ml | — |
| Osilodrostat (LCI699) 7 mg | LCI699 Exposures | Wk 8: 4h | 32 ng/ml | — |
| Osilodrostat (LCI699) 7 mg | LCI699 Exposures | Wk 8: Predose | 6.718 ng/ml | Geometric Coefficient of Variation 34.2 |
| Osilodrostat (LCI699) 7 mg | LCI699 Exposures | Wk 8: 1.5h | 32.1 ng/ml | — |
| Osilodrostat (LCI699) 7 mg | LCI699 Exposures | Wk 6: Predose | 8.065 ng/ml | Geometric Coefficient of Variation 8.6 |
Secondary
Percentage of Participants With Complete Response Rate (CRR)
Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN.
Time frame: Week 12, Week 24, Week 48, Week 72, last available assessment
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Osilodrostat (LCI699) | Percentage of Participants With Complete Response Rate (CRR) | Week 72 | 82.9 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Complete Response Rate (CRR) | Week 48 | 88.9 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Complete Response Rate (CRR) | Week 12 | 6.1 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Complete Response Rate (CRR) | Week 24 | 100 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Complete Response Rate (CRR) | Last available assess. | 69.4 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Complete Response Rate (CRR) | Week 48 | 77.1 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Complete Response Rate (CRR) | Week 12 | 91.4 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Complete Response Rate (CRR) | Week 24 | 97.1 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Complete Response Rate (CRR) | Week 72 | 83.3 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Complete Response Rate (CRR) | Last available assess. | 74.3 Percentage of participants |
| Non-randomized | Percentage of Participants With Complete Response Rate (CRR) | Last available assess. | 53.0 Percentage of participants |
| Non-randomized | Percentage of Participants With Complete Response Rate (CRR) | Week 72 | 78.0 Percentage of participants |
| Non-randomized | Percentage of Participants With Complete Response Rate (CRR) | Week 12 | 53.0 Percentage of participants |
| Non-randomized | Percentage of Participants With Complete Response Rate (CRR) | Week 48 | 48.5 Percentage of participants |
| Non-randomized | Percentage of Participants With Complete Response Rate (CRR) | Week 24 | 34.8 Percentage of participants |
Secondary
Percentage of Participants With Overall Response Rate (ORR)
Overall response rate is defined as percentage of enrolled participants with mUFC ≤ ULN or at least 50% reduction from baseline.
Time frame: Week 12, Week 24, Week 48, Week 72, last available assessment
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Osilodrostat (LCI699) | Percentage of Participants With Overall Response Rate (ORR) | Week 72 | 91.4 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Overall Response Rate (ORR) | Week 48 | 94.4 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Overall Response Rate (ORR) | Week 12 | 88.9 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Overall Response Rate (ORR) | Week 24 | 100 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Overall Response Rate (ORR) | Last available assess. | 91.7 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Overall Response Rate (ORR) | Week 48 | 88.6 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Overall Response Rate (ORR) | Week 12 | 97.1 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Overall Response Rate (ORR) | Week 24 | 97.1 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Overall Response Rate (ORR) | Week 72 | 96.7 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Overall Response Rate (ORR) | Last available assess. | 85.7 Percentage of participants |
| Non-randomized | Percentage of Participants With Overall Response Rate (ORR) | Last available assess. | 75.8 Percentage of participants |
| Non-randomized | Percentage of Participants With Overall Response Rate (ORR) | Week 72 | 80.5 Percentage of participants |
| Non-randomized | Percentage of Participants With Overall Response Rate (ORR) | Week 12 | 77.3 Percentage of participants |
| Non-randomized | Percentage of Participants With Overall Response Rate (ORR) | Week 48 | 59.1 Percentage of participants |
| Non-randomized | Percentage of Participants With Overall Response Rate (ORR) | Week 24 | 65.2 Percentage of participants |
Secondary
Percentage of Participants With Partial Response Rate (PRR)
Partial response rate is defined as percentage of enrolled participants with ≥ 50% reduction from baseline in mUFC, but mUFC\>ULN)
Time frame: Week 12, Week 24, Week 48, Week 72, last available assessment
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Osilodrostat (LCI699) | Percentage of Participants With Partial Response Rate (PRR) | Week 72 | 8.6 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Partial Response Rate (PRR) | Week 48 | 5.6 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Partial Response Rate (PRR) | Week 12 | 2.8 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Partial Response Rate (PRR) | Week 24 | 0.0 Percentage of participants |
| Osilodrostat (LCI699) | Percentage of Participants With Partial Response Rate (PRR) | Last available assess. | 22.2 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Partial Response Rate (PRR) | Week 48 | 11.4 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Partial Response Rate (PRR) | Week 12 | 5.7 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Partial Response Rate (PRR) | Week 24 | 0.0 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Partial Response Rate (PRR) | Week 72 | 13.3 Percentage of participants |
| LCI699 Placebo | Percentage of Participants With Partial Response Rate (PRR) | Last available assess. | 11.4 Percentage of participants |
| Non-randomized | Percentage of Participants With Partial Response Rate (PRR) | Last available assess. | 22.7 Percentage of participants |
| Non-randomized | Percentage of Participants With Partial Response Rate (PRR) | Week 72 | 2.4 Percentage of participants |
| Non-randomized | Percentage of Participants With Partial Response Rate (PRR) | Week 12 | 24.2 Percentage of participants |
| Non-randomized | Percentage of Participants With Partial Response Rate (PRR) | Week 48 | 10.6 Percentage of participants |
| Non-randomized | Percentage of Participants With Partial Response Rate (PRR) | Week 24 | 30.3 Percentage of participants |
Secondary
Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)
To assess the complete response rate at the end of individual dose-titration and treatment with LCI699 in the initial single-arm, open label period. A Key secondary efficacy responder is defined as a patient in FAS who has mUFC ≤ ULN at Week 24 and the dose of osilodrostat during Study Period 2 (Weeks 13-24) was not increased above the level established at the end of Study Period 1 (Week 12). Patients who had missing mUFC assessment at Week 24 will be counted as non-responders for the key secondary endpoint.
Time frame: Week 24
Population: Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osilodrostat (LCI699) | Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint) | 52.6 Percentage of participants |
Secondary
Time-to-escape
Escape was defined as the time (in days) from the first mUFC ≤ ULN to the first mUFC results \> 1.5 x ULN with at least 2 individual UFC results \> 1.5 x ULN the loss happened beyond 12-week dose titration period. Participants randomized to placebo were not included in the analysis.
Time frame: From the first mUFC ≤ ULN to the first mUFC results > 1.5 x ULN with at least 2 individual UFC results > 1.5 x ULN
Population: FAS comprised all enrolled patients who received at least one dose of osilodrostat. This is a subset of the FAS participants who met all the criteria for Escape. The placebo patients + patients that did not reach mUFC \<= ULN at some stage during the study are excluded from the denominator.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osilodrostat (LCI699) | Time-to-escape | 546.0 days |
Secondary
Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group
Time-to-loss of control of mUFC during the RW Period, defined as the time (in days) from randomization to the first evidence of loss of control (defined as mUFC assessment \>1.5 ULN based on central laboratory result & at least 2 of the associated individual urine samples showing UFC \>1.5×ULN) within the RW period. A patient without evidence of loss of control was censored at the date of the last assessment with mUFC ≤ 1.5 ULN. If a patient discontinued randomized treatment without having a UFC assessment, they were censored at the date of randomization. The measure type (number) refers to an Event probability estimate 8 weeks after randomization.
Time frame: 8 weeks after randomization
Population: Randomized analysis set (RAS): comprised all randomized patients who received at least one dose of randomized drug (osilodrostat or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osilodrostat (LCI699) | Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group | 5.6 Percentage |
| LCI699 Placebo | Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group | 61.1 Percentage |