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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这是一项1期、单中心、单剂量、剂量递增研究，旨在评估重组人酸性鞘磷脂酶(RhASM)治疗因ASM缺乏而导致的成人Niemann Pick病(NPD)的安全性、药代动力学和药效学。对于每个患者，研究参与将包括筛查/基线评估和登记阶段；72小时的住院时间，在此期间将进行单剂量重组人ASM输注；以及2842天的治疗后评估阶段，在注射后14天和28天进行跟踪评估，并进行42天的电话随访。至少有15名符合条件的成人(年龄在18岁到65岁之间)患者将被纳入这项研究。患者将根据脾肿大程度进行分层，以正常(MN)的倍数为单位，作为疾病严重程度的指标。将对五个单次递增剂量组进行安全性、PK和PD评估，每个组至少由3名患者组成。本研究选用的rhASM单剂剂量分别为0.03、0.1、0.3、0.6和1.0 mg/kg。剂量递增将按从最低剂量到最高剂量的顺序进行。所有患者将在注射重组人ASM后住院监测72小时，在第14天和第28天回来进行评估，并在第42天收到随访电话。72小时住院访问的安全监测将包括：不良事件(AE)报告、体检、生命体征(包括心率的持续监测)、临床实验室评估(血清化学、血液学、凝血检查、尿检)、肝功能测试(LFTs)和细胞因子。此外，还将在输液前和输液后的选定时间点进行肺功能测试(PFT)、肾上腺激素水平(每日和后促肾上腺皮质激素(ACTH)刺激测试醛固酮、皮质醇和β-4-雄烯二酮水平)、空腹血脂(FLP)、免疫原性测试、胸部X光、心电图(CG)、超声心动图(ECHO)、肝脏活检以及脾和肝脏的磁共振成像(MRI)。 假设：成人ASMD患者可以耐受单次递增剂量的rhASM。

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.