Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 89
- 试验地点
- 13
- 主要终点
- Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per Month
研究概览
简要总结
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that is caused by genetic mutations. It results in the uncontrolled growth of an unusual type of smooth muscle cell in the lung. These cells invade lung tissue, including the airways, blood vessels, and lymph vessels, and restrict the flow of air, blood, and lymph, respectively. Respiratory failure, lung collapse (pneumothorax), and pleural effusions (chylothorax) are hallmarks of the disease. This study will evaluate the safety and effectiveness of sirolimus, an inhibitor of the mTOR pathway, in stabilizing or improving lung function in people with LAM.
详细描述
LAM is an uncommon, progressive, cystic lung disease that predominantly affects young women. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes, which regulate cellular pathways that control nutrient sensing, cell size, cell migration, and cell proliferation. Individuals with LAM often experience pneumothorax and chylothorax, as well progressive loss of lung function. Sirolimus is drug that was approved for the prevention of kidney transplant rejection. It directly affects the cellular pathway that causes LAM. This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with LAM.
Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and month 24; and a volumetric computed tomography scan will occur at baseline, month 12, and month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Unlabeled sirolimus tablets were provided by Pfizer. Identical appearing placebo tablets were obtained from a commercial source. Sirolimus levels were reported only to the medical monitor. To maintain the blind, when dose adjustments were made in the sirolimus group, a sham adjustment was also made in the placebo group
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
- •Age 18 or older
- •Signed and dated informed consent
- •Diagnosis of LAM based on compatible chest CT scan and a) biopsy or cytology consistent with LAM, or b) presence of tuberous sclerosis, angiomyolipoma or chylous pleural effusion; or c) a VEGF-D level of at least 800 pg/ml
- •Forced expiratory volume in one second (FEV1) of 70% or less of predicted value after administration of a bronchodilator
排除标准
- •Known allergy to sirolimus
- •History of heart attack, angina, or stroke due to clogging, narrowing, and hardening of the arteries and blood vessels
- •Significant hematologic or hepatic abnormality (transaminase levels greater than three times the upper limit of normal, HCT less than 30%, platelets less than 80,000/cubic mm, adjusted absolute neutrophil count less than 1,000/cubic mm, total white blood cell count less than 3,000/cubic mm)
- •Intercurrent infection at the time treatment with sirolimus begins
- •Any surgery involving entry into a body cavity or requiring three or more sutures within 8 weeks of initiation of study drug
- •Use of an investigational drug within the 30 days prior to random assignment
- •Uncontrolled hyperlipidemia
- •Previous lung transplant or currently on lung transplant list
- •Unable to attend scheduled study visits
- •Unable to perform pulmonary function tests
- •Creatinine levels greater than 2.5 mg/dl
- •Chylous ascites severe enough to affect diaphragmatic function
- •Pleural effusion severe enough to affect pulmonary function, as determined by the study physician
- •History of acute pneumothorax within the 2 months prior to study entry
- •History of malignancy within the 2 years prior to study entry (except for squamous or basal cell skin cancer)
- •Use of estrogen containing medication within the thirty days prior to randomization
- •Unable or unwilling to use adequate contraception
- •Pregnant, breastfeeding, or plans to become pregnant within the next 2 years
研究组 & 干预措施
Active Agent (Sirolimus)
Participants receive sirolimus daily for 1 year and are followed with serial pulmonary function tests, 6-minute walk tests, and symptom and QOL questionnaires over a 2-year period.
干预措施: Sirolimus (Drug)
Placebo Arm
Participants receive placebo daily for 1 year and followed with serial pulmonary function tests, 6-minute walk tests, and symptom and QOL questionnaires over a 2-year period.
干预措施: Placebo (Drug)
结局指标
主要结局
Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per Month
时间窗: Baseline to Month 12
FEV1 values reported are in liters or milliliters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Normative ranges are determined in populations stratified by gender, height, age and race/ethnicity. Higher FEV1 values indicate better lung function.
次要结局
- Rate of Change in Diffusing Capacity for Carbon Monoxide (DLCO) in ml/Min/mmHg(Baseline to Month 12)
- Rate of Change in Six Minute Walk Distance in Meters/Month(Baseline to Month 12)
- Percent of Participants With Serious Adverse Events(Baseline to Month 12)
- Changes in FVC Slope in ml/Month(Baseline to Month 12)
- Rate of Change in Total Lung Volume in ml Per Month(Baseline to Month 12)
- Rate of Change in Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels in pg/ml Per Month(Baseline to Month 12)
研究者
Francis McCormack
Professor
University of Cincinnati