Sirolimus Therapy in Idiopathic and Lupus Membranous Nephropathy

西罗莫司治疗特发性和狼疮膜性肾病

• 批准号: 7967699
• 负责人: James Balow
• 金额: $ 10.76万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967699
• 关键词: 13 year old; Accounting; Acute; Adrenal Cortex Hormones; Adult; Adverse effects; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antigen-Antibody Complex; Basal cell carcinoma; Blood Pressure; Cardiovascular system; Child; Chlorambucil; Chronic; Complement Activation; County; Cyclophosphamide; Cyclosporine; Cyclosporins; Cystitis; Cytotoxic agent; Data Analyses; Detection; Deterioration; Discipline of Nursing; Disease remission; Dose; Drug Kinetics; Effectiveness; Enrollment; Equilibrium; Evaluation; FDA approved; Fibrosis; Glomerular Capillary; Glomerular Filtration Rate; Hour; Hypertension; Immune; Immunosuppressive Agents; Individual; Infection; Injury; Joints; Kidney; Kidney Diseases; Kidney Failure; Liver diseases; Lupus; Maintenance; Malignant Neoplasms; Mediating; Membranous Glomerulonephritis; Monitor; Mothers; National Heart, Lung, and Blood Institute; Nephrotic Syndrome; Nephrotoxic; Partial Remission; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Pilot Projects; Prednisone; Pregnancy; Pregnant Women; Prevention; Property; Proteinuria; Recruitment Activity; Recurrence; Renal function; Reporting; Reservations; Risk; Safety; Sirolimus; Skin; Systemic Lupus Erythematosus; Time Study; Toxic effect; Treatment Protocols; United States National Institutes of Health; Woman; age group; base; birth control; cancer diagnosis; cytopenia; effective therapy; glomerulosclerosis; infancy; interstitial; kidney allograft; men; older patient; prevent; standard care; treatment duration; 13 year old; Accounting; Acute; Adrenal Cortex Hormones; Adult; Adverse effects; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antigen-Antibody Complex; Basal cell carcinoma; Blood Pressure; Cardiovascular system; Child; Chlorambucil; Chronic; Complement Activation; County; Cyclophosphamide; Cyclosporine; Cyclosporins; Cystitis; Cytotoxic agent; Data Analyses; Detection; Deterioration; Discipline of Nursing; Disease remission; Dose; Drug Kinetics; Effectiveness; Enrollment; Equilibrium; Evaluation; FDA approved; Fibrosis; Glomerular Capillary; Glomerular Filtration Rate; Hour; Hypertension; Immune; Immunosuppressive Agents; Individual; Infection; Injury; Joints; Kidney; Kidney Diseases; Kidney Failure; Liver diseases; Lupus; Maintenance; Malignant Neoplasms; Mediating; Membranous Glomerulonephritis; Monitor; Mothers; National Heart, Lung, and Blood Institute; Nephrotic Syndrome; Nephrotoxic; Partial Remission; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Pilot Projects; Prednisone; Pregnancy; Pregnant Women; Prevention; Property; Proteinuria; Recruitment Activity; Recurrence; Renal function; Reporting; Reservations; Risk; Safety; Sirolimus; Skin; Systemic Lupus Erythematosus; Time Study; Toxic effect; Treatment Protocols; United States National Institutes of Health; Woman; age group; base; birth control; cancer diagnosis; cytopenia; effective therapy; glomerulosclerosis; infancy; interstitial; kidney allograft; men; older patient; prevent; standard care; treatment duration

This is a phase 2 trial to evaluate the safety and effectiveness of a new immunosuppressive drug, sirolimus, in patients with idiopathic and lupus membranous nephropathy. Patients (older than 13 years) were invited to participate if they had persistent nephrotic range proteinuria despite standard treatment with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. Patients with persistent nephrotic range proteinuria are at increased risk for renal function deterioration as well as cardiovascular and thromboembolic complications. The target blood pressure was less than 125/75, as recommended by the Sixth Report Joint National Commission on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (NHLBI, NIH). Children less than 13 years were excluded because at the time this study was initiated, sirolimus had not been approved by the FDA in this age group and because a complete pharmacokinetics profile was not available in this age group. Furthermore, patients with advanced renal insufficiency (estimated glomerular filtration rate less than 30 mL/min/1.73 m2) were excluded because we anticipated that sirolimus would most likely be beneficial before progressive glomerular sclerosis and interstitial fibrosis had become the dominant (and probably irreversible) abnormalities. Patients with active infections, uncontrolled hypertension, chronic liver disease, cytopenias and a cancer diagnosis or recurrence within the preceding 5 years (excluding basal cell carcinoma of the skin) were excluded. Pregnant women, nursing mothers and individuals (men and women) not practicing birth control were excluded because the safety of sirolimus during pregnancy and infancy had not been determined. Patients could not take immunosuppressive agents or experimental medications of any type during the two-month period prior to initiating sirolimus, with two exceptions. First, patients with lupus membranous nephropathy were permitted to have received modest doses of corticosteroids (no more than the equivalent of prednisone 10 mg/day) for control of extra-renal manifestations of SLE during the two-month period prior to starting sirolimus. Second, patients with worsening nephrotic syndrome were allowed to start sirolimus after a shorter interval off other immunosuppressive agents. The loading dose of sirolimus was 2 mg every 4 hours for 3 doses (total dose of 6 mg) on the first day for adults and children greater than or equal to 40 kg. The initial maintenance dose of sirolimus for these individuals was 2 mg once daily. The initial and maintenance doses were modified for smaller individuals. The dose of sirolimus was adjusted to achieve a target level of 5 - 15 ng/mL during the first 6 months of the treatment period. The target level was increased to 10 - 20 ng/mL during the second 6 months if a complete remission had not been achieved by the end of the first 6 months. The sirolimus dose was held and/or reduced if certain toxic side effects were observed. Renal function, the degree of proteinuria and side effects were monitored closely throughout the study. Twelve patients have entered this study, and all patients have completed treatment or were withdrawn from sirolimus treatment because of side-effects and lack of efficacy. Only two patients have achieved a partial remission. Consequently, we are no longer recruiting or enrolling subjects into this study. Study and data analyses are ongoing.

这是一项评估新免疫抑制药物Sirolimus对特发性和狼疮性膜性肾病患者的安全性和有效性的2期试验。 如果患者具有持续的肾病范围蛋白尿，则邀请患者参加，尽管具有血管紧张素的标准治疗，但可以转化酶抑制剂或血管紧张素受体阻滞剂。 持续的肾病范围蛋白尿患者的肾功能恶化以及心血管和血栓栓塞并发症的风险增加。 正如第六次报告的预防，检测，评估和治疗高血压的第六委员会的建议（NHLBI，NHLBI，NIH）的建议，目标血压小于125/75。 不到13岁的儿童是因为在本研究开始时，Sirolimus尚未获得该年龄段的FDA批准，并且由于该年龄段的完整药代动力学概况不可用。 此外，排除了晚期肾功能不全（估计的肾小球过滤率小于30 ml/min/1.73 m2）的患者，因为我们预计Sirolimus很可能在进行性肾小球硬化性硬化和间质纤维化之前很可能是有益的，并且是主流（可能是不可逆转的）异常。 排除了活跃感染，不受控制的高血压，慢性肝病，细胞质疾病以及在前5年内癌症诊断或复发的患者（不包括皮肤的基底细胞癌）。 由于未确定怀孕和婴儿期间西罗莫司的安全性，因此排除了孕妇，哺乳母亲和个人（男人和女性）不执行节育的情况。 在启动Sirolimus之前的两个月内，患者无法服用任何类型的免疫抑制剂或实验药物，但有两个例外。 首先，允许患有狼疮膜性肾病的患者在开始新西罗里木斯之前的两个月期间，以控制SLE的肾上腺外表现，以控制SLE的肾上腺外表现。其次，肾病综合征恶化恶化的患者被允许在其他免疫抑制剂的间隔较短后开始西罗里木斯。 成年人和大于或等于40 kg的成人和儿童的第一天，西罗里木斯的加载剂量每4小时每4小时（总剂量为6 mg）每4小时（总剂量为6 mg）。 这些人的初始维持剂量每天每天2 mg。 为较小的个体修改了初始剂量和维护剂量。 在治疗期的前6个月中，调整了西罗莫司的剂量，以达到5-15 ng/ml的目标水平。 如果在前6个月结束时尚未完全缓解，目标水平在第二个6个月内将目标水平提高到10-20 ng/ml。 如果观察到某些有毒的副作用，则将西洛里木剂量持有和/或减少。 在整个研究过程中，密切监测肾功能，蛋白尿程度和副作用。 十二名患者已经进入了这项研究，所有患者均已完成治疗或由于副作用和缺乏疗效而退出了西罗莫司治疗。 只有两名患者已获得部分缓解。 因此，我们不再招募或招募受试者参加这项研究。 研究和数据分析正在进行中。