An Exploratory, Open-label, Non-randomized, Within-patient Multiple Dose-escalation Safety, Tolerability, PK and Efficacy Trial of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 3
- 主要终点
- Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations
研究概览
简要总结
This was an exploratory study to determine whether escalating doses of RAD001 (everolimus) were safe and effective in patients with Lymphangioleiomyomatosis
详细描述
In addition to the data collected in this study, historical data from 43 patients treated with placebo from the multicenter trial of sirolimus in LAM (MILES) study (NCT00414648) were down weighted to an effective sample size of 18 for comparison of FEV1 and FVC endpoints. Reference to the publication of the MILES study has been provided under "Result Publication".
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female aged >/= 18 years with a diagnosis of LAM
- •Pulmonary function abnormalities as follows:
- •FEV1 of ≤ 80% of the predicted value following administration of a standard dose of a short acting β2-agonist (*200 µg Salbutamol, measured between 10 and 15 minutes of inhalation) OR
- •FEV1 < 90% of the predicted value of bronchodilator following administration of a standard dose of a short acting β2-agonist (*200 µg Salbutamol, measured between 10 and 15 minutes of inhalation) and DLco (uncorrected) <80% predicted.
- •Female patients including those of childbearing potential will be included in this study.
- •Negative pregnancy test at screening and baseline
排除标准
- •FEV1<50% of predicted post-bronchodilator.
- •Change in FVC (ml) > ± 15% of screening value at baseline visit (not less than 14d after screening visit).
- •Use of any medicine containing estrogen in the 4 months prior to the screening visit and for the duration of the study
- •Significant hematologic, renal, hepatic laboratory abnormality or amylase > 1.5x the upper limit of the normal range at the screening or baseline visits
- •Fasting blood glucose > 126mg/dl or random blood glucose >200mg/dl at screening and/or baseline
- •Recent surgery (involving entry into a body cavity or requiring sutures) within 2 months of the screening visit or any evidence of unhealed surgical wound.
- •Uncontrolled hyperlipidemia (defined as persistent elevation of total cholesterol or triglycerides >6.5nM/L) or a history of clinical atherosclerotic disease including heart attack, angina, peripheral vascular disease or stroke.
- •Previous organ transplantation
- •Inability to give informed consent
- •Inability to perform pulmonary function or 6 minute walk tests and imaging assessments
- •Other protocol-defined inclusion/exclusion criteria may apply
研究组 & 干预措施
Everolimus
All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks.
The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.
干预措施: Everolimus (Drug)
结局指标
主要结局
Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations
时间窗: Baseline, 26 weeks
Blood samples (1 mL) for determination of VEGF-D were collected from a forearm vein (direct venipuncture or from an indwelling cannula) and 2 aliquots of serum were collected. VEGF-D levels were determined from only 1 of the 2 serum aliquots, with the second acting as a back-up. A serum VEGF-D \>800 pg/mL level supports a diagnosis of Lymphangioleiomyomatosis (LAM)
Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State
时间窗: pre-dose and at 2 hour post dose at week 26
Venous blood samples (2 mL) for pharmacokinetic evaluation were collected pre dose and 2 hours post dose at preselected visits.
次要结局
- Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity(Baseline, 26 weeks)
- Change From Baseline in Forced Vital Capacity (FVC)(Baseline, 26 weeks)
- Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)(Baseline, 26 weeks)
- Change From Baseline in Extended Pulmonary Function Testing(Baseline, 26 weeks)
- Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO)(Baseline, 26 weeks)
- Change From Baseline in Oxygen Saturation(Baseline, 26 weeks)