CLINICAL TRIAL: A MULTICENTER OPEN-LABEL STUDY OF GENE-ACTIVATED HUMAN GLUCOCERE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这是一项II/III期开放标签研究，旨在评价GA-GCB治疗既往接受伊米苷酶治疗的I型戈谢病患者的安全性。 最初将根据患者的已知病史筛选患者是否参与研究。 患者必须在研究入组前6个月内接受相同的伊米苷酶剂量和给药方案，并且必须具有至少30个月的总体伊米苷酶治疗期。 迄今为止，尚未定义或推荐伊米苷酶的标准剂量;因此，无法确定参与本研究的患者的最佳或标准治疗剂量。 最常用的治疗剂量为15 U/kg至60 U/kg。 为了评价每隔一周给予15 U/kg至60 U/kg剂量的GA-GCB治疗的安全性，本研究将入组在这些剂量和剂量之间接受伊米苷酶治疗至少30个月的患者。 患者必须在研究入组前6个月内接受相同的伊米苷酶剂量和给药方案。 入组本研究的患者的12个月GA-GCB治疗期将允许评价每隔一周给予15 U/kg至60 U/kg剂量的GA-GCB治疗的安全性。 本研究的次要目的是评价GA-GCB治疗12个月期间临床参数（血红蛋白浓度、血小板计数以及肝脏和脾脏体积）的变化。 如果不考虑既往接受伊米苷酶治疗患者的其他疗效数据，则难以评估这些参数。 根据专家顾问的临床经验确定了拟定的12个月评价时间范围，这表明患者在未接受ERT治疗3个月后，临床参数的改善可能逆转。 对于每个临床活动参数，备择假设是较基线的平均变化（即，伊米苷酶治疗结束时）至第12个月的受试者的平均体重在待评价参数的规定临床显著水平内（其中血红蛋白较基线的群体平均变化在1 g/dL范围内，血小板计数在20%范围内，肝脏和脾脏体积在15%范围内。 对于这些临床参数较基线的真实差异，将使用双侧90%置信区间进行评价。 例如，如果血红蛋白较基线变化的置信区间在1 - 1 g/dL范围内，则可得出GA-GCB的疗效结论。 我们的假设是平均血红蛋白浓度在12个月内基本保持不变。 本研究的把握度计算基于TKT 025的结果，检查了基线平均值和患者内较基线的变化标准差。 由于本研究将在世界各地的研究中心进行，预计将代表广泛的疾病严重程度。 由于GA-GCB在TKT 025中具有可接受的安全性特征，因此至少2岁且不存在3型戈谢病高风险的儿童将有资格入组。 在TKT 025治疗的9个月期间和TKT 025 EXT治疗的前6个月期间，共计15个治疗月，没有抗体形成。 此外，如前所述，迄今为止尚未发生药物相关严重不良事件，仅发生轻度、一过性输注相关不良事件。 因此，治疗2至17岁的患者是合理的。

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 II/III open-label study designed to evaluate the safety of GA-GCB therapy for patients with type I Gaucher disease who previously received imiglucerase. Patients will initially be screened for study participation based on their known medical histories. Patients must have received the same imiglucerase dose and dose regimen during the 6 months prior to study enrollment and must have had an overall imglulcerase treatment period of at least 30 months. To date, no standard dose has been defined or recommended for imiglucerase; therefore, an optimal or standard treatment dose for patients participating in this study could not be identified. Treatment at doses between 15 U/kg and 60 U/kg are most frequently used. In order to evaluate the safety of GA-GCB treatment at doses between 15 U/kg and 60 U/kg administered every other week, this study will enroll patients who have been treated with imiglucerase for at least 30 months at and between those doses. Patients must have been receiving the same imiglucerase dose and dose regimen during the 6 months prior to study enrollment. The 12 month treatment period with GA-GCB for patients enrolled into this study will allow evaluation of the safety of GA-GCB treatment at doses between 15 U/kg and 60 U/kg given every other week. The secondary objectives of the study are to evaluate changes in clinical parameters (hemoglobin concentration, platelet count, and liver and spleen volumes) throughout the 12 months of GA-GCB treatment. These parameters would be difficult to assess without considering additional efficacy data from patients previous treatment with imiglucerase. The proposed 12 month time frame for evaluation was determined based on clinical experience of expert consultants, which indicates that patients would likely have a reversal of improvement in clinical parameters after 3 months of receiving no ERT treatment. For each clinical activity parameter, the alternative hypothesis is that the mean change from Baseline (i.e., the end of imiglucerase treatment) to Month 12 is within the specified clinically significant levels for the parameters to be evaluated (where the population mean change from Baseline for hemoglobin is within 1 g/dL, the platelet count is within 20%, and the liver and spleen volumes are within 15%. This will be evaluated using a 2-sided 90% confidence interval for the true difference from Baseline for these clinical parameters. For example, efficacy of GA-GCB will be concluded if the confidence interval for the change from Baseline of hemoglobin is within the interval 1 to 1 g/dL. Our assumption is that the mean hemoglobin concentration will be essentially constant over the 12 month period. The power calculations for this study were based on results of TKT025, examining the Baseline mean values and the within patient change from Baseline standard deviations. As the study will be conducted at sites across the world, it is expected that a broad range of disease severity will be represented. Children who are a minimum of 2 years old who are not at high risk for type 3 Gaucher disease will be eligible for enrollment, as GA-GCB had an acceptable safety profile in TKT025. There was no antibody formation during 9 months of treatment in TKT025 and the first six months on TKT025EXT for a total of 15 treatment months. In addition, as has been previously discussed, there have been no drug related serious adverse events to date and only mild, transient infusion-related adverse events. Therefore, it is reasonable to treat patients 2 to 17 years old.