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

临床试验：基因激活人类葡萄糖的多中心开放标签研究

• 批准号: 7950654
• 负责人: Christine Eng
• 金额: $ 0.12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950654
• 关键词: 17 year old; 2 year old; Adverse event; Antibody Formation; Child; Clinical; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Confidence Intervals; Data; Dose; Enrollment; Evaluation; Funding; Gaucher Disease; Genes; Grant; Hemoglobin; Human; Infusion procedures; Institution; Liver; Medical History; Patients; Pharmaceutical Preparations; Phase; Platelet Count measurement; Population; Research; Research Design; Research Personnel; Resources; Safety; Serious Adverse Event; Severity of illness; Side; Site; Source; Specific qualifier value; Spleen; Subacute Neuronopathic Gaucher Disease; Time; Treatment Protocols; United States National Institutes of Health; base; clinically significant; experience; high risk; imiglucerase; open label; standard care; treatment duration

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 这是一项 II/III 期开放标签研究，旨在评估 GA-GCB 治疗对既往接受过伊米苷酶治疗的 I 型戈谢病患者的安全性。 最初将根据患者已知的病史筛选是否参与研究。 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剂量方案，并且必须接受至少 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。 为了评估每隔一周给予 15 U/kg 至 60 U/kg 剂量的 GA-GCB 治疗的安全性，本研究将招募在这些剂量和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剂量方案。 参加本研究的患者接受 12 个月的 GA-GCB 治疗期，可以评估每隔一周给予 15 U/kg 至 60 U/kg 剂量的 GA-GCB 治疗的安全性。 该研究的次要目标是评估 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。 如果不考虑之前接受伊米苷酶治疗的患者的额外疗效数据，这些参数将很难评估。 建议的12个月评估时间框架是根据专家顾问的临床经验确定的，这表明患者在不接受ERT治疗3个月后，临床参数的改善可能会出现逆转。 对于每个临床活动参数，备择假设是从基线（即伊米苷酶治疗结束）到第 12 个月的平均变化在待评估参数的指定临床显着水平之内（其中血红蛋白相对于基线的群体平均变化在 1 g/dL 以内，血小板计数在 20% 以内，肝脏和脾脏体积在 15% 以内）。这将使用 2 面评估 这些临床参数与基线的真实差异的 90% 置信区间。 例如，如果血红蛋白相对于基线的变化的置信区间在 1 至 1 g/dL 的区间内，则可以得出 GA-GCB 的功效。 我们的假设是平均血红蛋白浓度在 12 个月期间基本保持不变。 本研究的功效计算基于 TKT025 的结果，检查基线平均值 以及患者内部相对于基线标准差的变化。 由于该研究将在世界各地进行，预计将代表广泛的疾病严重程度。 由于 GA-GCB 在 TKT025 中具有可接受的安全性，因此年龄不小于 2 岁、患 3 型戈谢病风险不高的儿童将有资格参加。 TKT025 治疗的 9 个月和 TKT025EXT 治疗的前 6 个月，总共 15 个月的治疗期间没有抗体形成。 此外，正如之前所讨论的，迄今为止还没有与药物相关的严重不良事件，只有轻微的、短暂的输注相关不良事件。 因此，治疗2岁至17岁的患者是合理的。