Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease
- Conditions
- Cushing's Disease
- Interventions
- Registration Number
- NCT02697734
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The purpose of this study was to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy.
- Detailed Description
The study LCI699C2302 (LINC-4) is a multi-center, randomized, double-blind study to evaluate the safety and efficacy of osilodrostat in patients with Cushing's disease.
Enrolled patients were initially randomized to either osilodrostat or placebo, in a 2:1 ratio, for a 12-week double-blind period (Period 1). Randomization was stratified by history of pituitary radiation. After Week 12, all patients received open-label osilodrostat until the end of the Core phase at Week 48 (Period 2).
After Week 48, patients could join an optional 48 week extension period.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 73
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description osilodrostat Group osilodrostat Participants in this arm were randomized to receive the study drug, osilodrostat followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration) osilodrostat Placebo Group osilodrostat Placebo Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration)
- Primary Outcome Measures
Name Time Method Percentage of Randomized Participants With a Complete Response at Week 12 A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12.
Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected Baseline, week 48 The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement.
Change in Triglyceride Baseline, weeks 12, 36, and 48 Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Change in Supine Systolic Blood Pressure Baseline, weeks 12, 36, and 48 Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Change in Standing Diastolic Blood Pressure Baseline, weeks 12, 36, and 48 Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Change in Supine Diastolic Blood Pressure Baseline, weeks 12, 36, and 48 Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Change in Weight Baseline, weeks 12, 36, and 48 Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm
Change in Waist Circumference Baseline, weeks 12, 36, and 48 Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease baseline, Week 12, Week 36 and Week 48 Change from baseline to Week 12, Week 36, and Week 48 in each of the following clinical signs of Cushing's disease, captured by: a semi-quantitative Likert scale for facial rubor, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises) by randomized treatment arm. The number/proportion of participants with an improvement or no change compared to baseline are reported
Percentage of Participants With mUFC ≤ ULN at Week 36 At Week 36 The complete response rate in both arms combined at Week 36. A complete responder at Week 36 is defined as a participant who had mean urine free cortisol \<= upper limit of normal (mUFC \<= ULN) at Week 36. Participants with missing mUFC at Week 36 were counted as non-responders.
Change From Baseline in mUFC Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96 To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.
Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN up to 12 weeks To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period.
Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response up to 12 weeks To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period.
Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.
The median time-to-first control and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).Time-to-first Control of mUFC - % Event Probability Estimates up to 12 weeks To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period.
Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.
% Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. % Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for Confidence Interval (CI) of Kaplan-Meier (KM) estimates.Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates week 26 and week 36 Escape is defined as the first loss of control of urinary free cortisol (UFC) that meets all of the following criteria: 1. prior normalization of UFC has occurred (median urinary free cortisol (mUFC)≤ upper limit of normal (ULN)); 2. patient reached the highest tolerated dose of osilodrostat; 3. 2 consecutive mUFC (collected at scheduled visits) were above 1.3x ULN; 4. the loss of control of UFC is not related to a dose interruption or dose reduction due to safety reasons; 5. happened beyond Week 26 when the patients have a chance to be treated with doses as high as 30 mg bid.
* Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point.
* Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for CI of KM estimates.Change in Fasting Plasma Glucose Baseline, weeks 12, 36, and 48 Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants up to 48 weeks To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC \> 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks.
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected Baseline, week 48 The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement. T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient. The WHO criteria are: Normal is a T-score of -1.0 or higher"
Change in Hemoglobin A1C Baseline, weeks 12, 36, and 48 Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC from week 26 to week 48 To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC \> 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks.
The median time-to-escape and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).Change in HDL Cholesterol Baseline, weeks 12, 36, and 48 Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').
The questionnaire consists of 12 items measured on a five 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 week. 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. Increases from baseline are indicative of an improvement.Change From Baseline in EQ-5D VAS Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with 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 EQ-5D-5L VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 baseline, week 12, 36 and 48 Overall response rate defined as percentage of complete responders (mUFC ≤ ULN) plus partial responders (≥ 50% reduction in mUFC from baseline and \>ULN) at week 12, 36, 48 by treatment arms for all patients.
Change in LDL Cholesterol Baseline, weeks 12, 36, and 48 Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Change From Baseline in EQ-5D-5L Utility Index Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. 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. 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, and 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.Change From Baseline in Beck Depression Inventory-II - Total Score Derived Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. The Beck Depression Inventory II (BDI-II) is a patient reported instrument that consists of 21 items designed to assess the intensity of depression in clinical and normal patients in the preceding two weeks. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. A global score ranges from 0 to 63 and 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. A reduction from baseline in BDI-II is indicative of an improvement.
Change From Baseline in Serum Cortisol Baseline, Week 12, Week 36, Week 48 Change from baseline in serum cortisol
Change From Baseline in Late Night Saliva Cortisol Baseline, Week 12, Week 36, Week 48 Change from baseline in late night saliva cortisol (nmol/L)
Change From Baseline in Morning Saliva Cortisol Baseline, Week 12, Week 36, Week 48 Change from baseline in morning saliva cortisol (nmol/L)
Change From Baseline in Hair Cortisol Levels Baseline, Week 26, Week 48 Change from baseline in hair cortisol levels
Plasma Osilodrostat Concentrations (ng/mL) pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26 Plasma osilodrostat concentrations (ng/mL)
Change in Cholesterol Baseline, weeks 12, 36, and 48 Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Change in Standing Systolic Blood Pressure Baseline, weeks 12, 36, and 48 Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').
The questionnaire consists of 12 items measured on a five 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 week. 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. Increases from baseline are indicative of an improvement.Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').
The questionnaire consists of 12 items measured on a five 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 week. 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. Increases from baseline are indicative of an improvement.
Trial Locations
- Locations (7)
Novartis Investigative Site
🇹🇷Kocaeli, Turkey
Columbia University Medical Center New York Presbyterian Neuroendocrine Unit
🇺🇸New York, New York, United States
University of Colorado Endocrinology Clinical Trials Unit
🇺🇸Aurora, Colorado, United States
Oregon Health and Science University SC LCI699C2301
🇺🇸Portland, Oregon, United States
University of Pennsylvania Medical Center University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States