A Proof of Concept, Open-label, Forced Titration, Multi-center Study to Assess the Safety/Tolerability and Efficacy of 10-weeks Treatment of LCI699 in Patients With Cushing's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 5
- 主要终点
- Percentage of Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10
研究概览
简要总结
This exploratory study is a proof of concept study to determine whether LCI699 can safely reduce the level of urinary free cortisol in patients with Cushing's disease.
In addition, this study evaluated the long term efficacy and safety of LCI699 including an additional 12 week of treatment followed by a 12 month long term optional extension.
A second extension provided patients who were clinically benefitting from LCI699 an opportunity to continue to have access to the drug until LCI699 was commercially available and reimbursed or through the availability of a local access program.
详细描述
The Primary objective of this study was to assess the effect of 10-week treatment osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing's disease.
The study consisted of a screening period of up to 60 days (to allow an adequate washout period for any medications that modified cortisol levels), a 10-14-day baseline period, a 10-week sequential dose escalation treatment period and a 14-day washout period followed by a Study Completion evaluation approximately 14 days after the last drug administration. Twelve patients were recruited and completed Part l of the study.
Eligible patients were dosed at 2 mg b.i.d for the first two weeks, the dose could then be increased every two weeks as necessary (to doses of 5, 10, 20 and 50 mg b.i.d). If at anytime, the subject's UFC was < Upper Limit of Normal (ULN), dose escalation was halted and the subject remained on the current, efficacious dose through Week 10, with continued monitoring of UFC responses every 2 weeks to allow continued dose adjustments if necessary. If at any time the subject experienced side effects which were either intolerable or met dose adjustment criteria, the prescribed dose was adjusted.
The primary endpoint (UFC ≤ ULN or ≥50% decrease at Day 70) was achieved by all patients. Subsequently, in order to confirm these observations, protocol was amended (Protocol amendment 4) and new patients were enrolled and investigated for a longer treatment period.
Following Protocol amendment 4, the study design was modified to include patients in Part II of the study for evaluating the long-term efficacy and safety of osilodrostat treatment for 22 weeks. Nineteen patients (15 who were treated in the expansion cohort in Part ll and 4 who participated in Part l) with Cushing's disease were enrolled as part of the Expansion cohort in Part II of the study. The 12 patients who had entered the study in Part I, were allowed to re-enter the study as the Core proof of concept (PoC) Follow-up cohort. At Day 70 ± 2 days (Week 10), all patients (both patients entering for the first time and those reentering the study) entered the 12-week assessment period. At Day 154, patients completed the End of Treatment-Core visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •Patients with a confirmed diagnosis of Cushing's Disease (persistent or recurrent) as evidenced by increased 24-hour urine free cortisol (UFC), normal or increased morning plasma Adrenocorticotropic Hormone (ACTH), and pituitary origin of excess ACTH.
- •Patients with de novo Cushing's disease can be included only if they are not considered candidate for surgery
排除标准
- •Patients treated with mitotane 6 months prior to Visit 1
- •Patients with compression of the optic chiasm
- •Patients with a known inherited syndrome as the cause for hormone over secretion
- •Patients with Cushing's syndrome due to ectopic ACTH secretion or adrenal Cushing's syndrome
- •Patients with pseudo-Cushing's syndrome
- •Patients who are not biochemically euthyroid
- •Diabetic patients with poorly controlled diabetes (HbA1c >9%)
- •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 who have received pituitary irradiation within five years prior to Visit
- •Patients with risk factors for QTc prolongation or Torsade de Pointes.
研究组 & 干预措施
Part l: Core cohort
Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part I of this study. 4 patients in this cohort moved to Part II of the study
干预措施: LCI699 (Drug)
Part II Core: Expansion cohort
Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Expansion of this study. These patients were all newly enrolled into the phase II part of the study
干预措施: LCI699 (Drug)
Part II Core: Follow-up cohort
Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Follow-up of this study. These patients were patients who transferred from Part I Core phase of the study
干预措施: LCI699 (Drug)
结局指标
主要结局
Percentage of Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10
时间窗: 10 weeks
A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 10 was ≤ Upper Limit of Normal (ULN), as defined by the local laboratories, or represented a ≥50% decrease from baseline. Patients who discontinued for a disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels were higher than the normal limit and experienced \<50% decrease in UFC were classified as non-responders.
次要结局
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: LH (Male)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Sitting Diastolic Blood Pressure (DBP), Sitting Systolic Blood Pressure (SBP)(Baseline, Week 22, Week 70, Last observed value, up to Month 88)
- Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Weight(Baseline, Week 22, Week 70, Last observed value, up to Month 88)
- Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Body Mass Index (BMI)(Baseline, Week 22, Week 70, Last observed value, up to Month 88)
- Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Quantitative Insulin Sensitivity Check Index (QUICKI)(Baseline, Week 22, Week 70, Last observed value, up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of Hypothalamic-Pituitary-Adrenal (HPA)-Axis: 11- Deoxycorticosterone (Overall)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: 11-Deoxycortisol (Overall)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Aldosterone, Thyroxine, Free (T4)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Female)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Male)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (FSH) (Female)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (Male)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Renin, Insulin, Thyrotropin(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Insulin-like Growth Factor-1(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Luteinising Hormone (LH) (Female)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Female)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Male)(baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88)
- Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Fasting Glucose(Baseline, Week 22, Week 70, Last observed value, up to Month 88)
- Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Hemoglobin A1C (HbA1C) (Glycosylated Hemoglobin)(Baseline, Week 22, Week 70, Last observed value, up to Month 88)
- Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides(Baseline, Week 22, Week 70, Last observed value, up to Month 88)
- Pharmacokinetics (PK) Parameters: Area Under Curve (AUC)0-6h ss, AUC0-12h ss(pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose)
- PK Parameters: Cmax ss, Ctrough ss(pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose)
- PK Parameters: Tmax ss,(pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose)
- PK Parameters: T1/2 ss,(pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose)
- Percentage of Participants Who Were Responders on 24-hour Urine Free Cortisol (UFC) at Week 22(Week 22)
- Number of Participants With Escape(approx. 7 years)