Phase III, Multi-center, Double-blind, Randomized Withdrawal Study of LCI699 Following a 24 Week, Single-arm, Open-label Dose Titration and Treatment Period to Evaluate the Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 137
- 试验地点
- 13
- 主要终点
- Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be obtained before any assessment is performed.
- •Male or female patients aged 18 - 75 years.
- •Patients must have confirmed Cushing's disease that is persistent or recurrent.
- •Patients with a history of prior pituitary surgery must be at least 30 days post-surgery to be eligible for inclusion in this study.
- •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.
- •Patients with de novo Cushing's disease can be included only if they are not considered candidates for surgery.
- •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.
- •Patients are permitted to washout current drug therapy to meet these entry criteria if they have a known diagnosis of Cushing's disease.
排除标准
- •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.
- •History of hypersensitivity to LCI699 or to drugs of similar chemical classes.
- •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.
- •Patients with risk factors for QTc prolongation or Torsade de Pointes.
- •Pregnant or nursing (lactating) women.
- •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.
- •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).
- •Patients who have a known inherited syndrome as the cause for hormone over secretion.
- •Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH-independent (adrenal) Cushing's syndrome.
- •Patients who have undergone major surgery within 1 month prior to screening.
- •Hypertensive patients with uncontrolled blood pressure.
- •Diabetic patients with poorly controlled diabetes.
- •Patients who are not euthyroid as judged by the investigator.
- •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.
- •Patients with moderate to severe renal impairment.
- •Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with defined elevated ALT/ AST/ Bilirubin.
- •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.
- •Patients who have a history of alcohol or drug abuse in the 6 month period prior to study treatment.
- •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.
研究组 & 干预措施
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.
干预措施: osilodrostat (Drug)
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.
干预措施: LCI699 matching placebo (Drug)
结局指标
主要结局
Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata
时间窗: 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
次要结局
- Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group(8 weeks after randomization)
- Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)(Week 24)
- Complete Response Rate (CRR)(Week 12, Week 24, Week 48, Week 72, last observed value)
- 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 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 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 From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight(Baseline, Weeks 48, 72, last available assessment)
- 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 From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference(Baseline, Weeks 48, 72, last available assessment)
- 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)
- Actual Change From Baseline in mUFC(Weeks 12, 24, 48, 72, last available assessment)
- Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose(Baseline, Weeks 48, 72, last available assessment)
- Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)(Baseline, W48, W72, Last available assessment)
- Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index(Baseline, W48, W72, Last available assessment)
- Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS)(Baseline, W48, W72, Last available assessment)
- Change From Baseline in the Physical Features of Cushing's Disease by Photography(Week 48, Week 72, Last available assessment)
- Change From Baseline in Bone Mineral Density - All Participants(Baseline, Week 48, Last observed value (LOV))
- 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)
- LCI699 Exposures(from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose)
- Percentage of Participants With Partial Response Rate (PRR)(Week 12, Week 24, Week 48, Week 72, last available assessment)
- Percentage of Participants With Complete Response Rate (CRR)(Week 12, Week 24, Week 48, Week 72, last available assessment)
- Percentage of Participants With Overall Response Rate (ORR)(Week 12, Week 24, Week 48, Week 72, last available assessment)