CLINICAL TRIAL: RHASM IN ADULTS WITH ACID SPHINGOMYELINASE DEFICIENCY (ASMD)

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 这是一项I期、单中心、单次给药、剂量递增研究，旨在评价重组人酸性鞘磷脂酶（rhASM）在由于ASM缺乏导致的尼曼匹克病（NPD）成人患者中的安全性、药代动力学和药效学。 对于每例患者，研究参与将包括筛选/基线评价和入组阶段; 72小时住院治疗，在此期间将进行rhASM单次给药输注;以及2842天治疗后评估阶段，在输注后14天和28天进行随访评估，并进行42天电话随访。 本研究将入组至少15例合格成人（18 - 65岁，含）患者。 患者将按照脾肿大程度（正常值的倍数（MN））分层，作为疾病严重程度的指标。 将评价5个递增单剂量组（每组至少3例患者）的安全性、PK和PD。 本研究选择的rhASM单次剂量为0.03、0.1、0.3、0.6和1.0 mg/kg。 剂量递增将从最低剂量到最高剂量顺序进行。 所有患者将在rhASM输注后住院监测72小时，在第14天和第28天返回进行评估，并在第42天接受电话随访。 72小时住院访视期间的安全性监测将包括：不良事件（AE）报告、体格检查、生命体征（包括持续监测心率）、临床实验室评价（血清化学、血液学、凝血研究、尿分析）、肝功能检查（LFT）和细胞因子。 此外，肺功能测试（PFT）、肾上腺激素水平（用于醛固酮、皮质醇和δ-4-雄烯二酮水平的昼夜和促肾上腺皮质激素（ACTH）刺激后测试）、空腹血脂谱（FLP）、免疫原性测试、胸部X射线、心电图（ECG）、超声心动图（ECHO）、肝活检，在输注前和输注后的选定时间点进行脾脏和肝脏的磁共振成像（MRI）。 假设：将递增剂量的rhASM作为单次剂量给予ASMD成人将是耐受的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a Phase 1, single-center, single-dose, dose escalation study to evaluate the safety, pharmacokinetics and pharmacodynamics of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann Pick disease (NPD) due to ASM deficiency. For each patient, study participation will consist of a screening/baseline evaluation and enrollment phase; a 72-hr in-patient stay during which a single-dose infusion of rhASM will be administered; and a 2842-day post-treatment assessment phase with follow-up assessments at 14 and 28 days post-infusion and a 42-day follow-up phone call. A minimum of 15 eligible adult (age 18 to 65 years, inclusive) patients will be enrolled into the study. Patients will be stratified by the degree of splenomegaly in multiples of normal (MN), as an indicator of disease severity. Five ascending single-dose groups, consisting of a minimum of 3 patients each, will be evaluated for safety, PK and PD. The single doses of rhASM selected for this study are 0.03, 0.1 0.3, 0.6 and 1.0 mg/kg. Dose escalation will proceed sequentially from lowest to highest dose. All patients will be monitored on an in-patient basis for 72 hr following the infusion of rhASM, return for assessments on Days 14 and 28 and receive a follow-up phone call on Day 42. Safety monitoring over the 72-hr in-patient visit will include: adverse event (AE) reporting, physical examinations, vital signs (including continuous monitoring of heart rate), clinical laboratory evaluations (serum chemistries, hematology, coagulation studies, urinalysis), liver function tests (LFTs), and cytokines. In addition, pulmonary function testing (PFT), adrenal hormone levels (diurnal and post-adrenocorticotropic hormone (ACTH) stimulation testing for aldosterone, cortisol, and delta-4-androstenedione levels), fasting lipid profile (FLP), immunogenicity testing, chest X-Rays, electrocardiograms (ECG), echocardiograms (ECHO), liver biopsies, and magnetic resonance imaging (MRI) of the spleen and liver will be performed at selected time points pre- and post-infusion. Hypothesis: Ascending doses of rhASM administered as a single dose to adults with ASMD will be tolerated.