A Two-Stage, Phase 1/2, Open-Label Study of the Human Insulin Receptor Monoclonal Antibody-Human Alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein, AGT-181 in Patients With Mucopolysaccharidosis I (MPS I, Hurler Syndrome)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- ArmaGen, Inc
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Stage 1: number of patients with adverse events as a measure of safety and tolerability of a single dose
研究概览
简要总结
AGT-181 is a fusion protein containing alpha-L-iduronidase that is intended to deliver the enzyme peripherally and to the brain, when administered intravenously. This is a safety and tolerability study to obtain safety and exposure data as well as information on the biological activity of the investigational drug.
This is a two-stage, sequential, single and multi-dose study of AGT-181 in patients with MPS I. The first stage will be an open-label, single-dose, dose-escalation cohort study and the second stage will be an open-label, multi dose, adaptive dose escalation cohort study.
详细描述
Stage 1:
Stage one will be a single-dose, dose-escalation study in cohorts of 2 patients with Hurler-Scheie or Scheie syndrome age 18 or greater who have not had ERT for at least 7 days prior to starting treatment. Approximately 3 cohorts will be enrolled sequentially, with safety data from the previous cohort being reviewed prior to escalation to the next higher dose cohort. Patients will be assigned to cohorts on the basis of their order of entry into the study.
The first cohort will be administered a single intravenous infusion of 0.3 mg/kg AGT-181 diluted in D5 normal saline over 4 hours. All patients will be observed for safety for 28 days after dosing. For dose escalation, the decision to proceed to a higher dose of AGT-181 will be made by the Sponsor and the investigator(s) after review of the available safety and tolerability data on or after 7 days post dose from patients who received the previous dose.
Dose escalation to a higher dose cohort can occur providing there are no dose limiting toxicities (DLT), defined as Grade 3 (severe or medically significant but not immediately life threatening) or higher adverse event according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Stage 2:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written consent and assent as required
- •Diagnosis of MPS 1 confirmed by clinical signs and symptoms, documented fibroblast or leukocyte IDUA enzyme activity of less than 10% the lower limit of normal
- •Female patients must not be pregnant, willing to utilize appropriate birth control methods and undergo pregnancy testing during the study
- •if taking standard ERT, must be willing to discontinue for 1 week prior to dosing and for the study duration
- •Additional Inclusion Criteria, Stage 1:
- •18 years of age or older
- •must have a diagnosis of Hurler-Scheie or Scheie syndrome
- •Additional Inclusion Criteria, Stage 2:
- •2 years of age or older (and less than 18)
- •must be willing to undergo CNS testing, including assessment of CSF via lumbar puncture, MRI scans and neurocognitive testing
- •must have evidence of Hurler-Scheie or Scheie with CNS involvement, as evidence by:
- •score of 1 to 3 standard deviations below mean on IQ testing (i.e. IQ=55 or more) or in one domain of neuropsychological function (language, memory, non-verbal ability) OR
- •documented historical evidence of a decline greater than 1 standard deviation on sequential testing, OR
- •score between 0.75 and 1 standard deviation below the mean, AND cognitive deficit affects daily performance
排除标准
- •Refusal to complete all assessments
- •Pregnant or Lactating
- •Received investigational drug within 1 year prior to study enrollment
- •Medical condition or extenuating circumstance that, in the opinion of the investigator, may interfere with study compliance
- •CSF pressure greater than 25 cm H20 (18 mm Hg)
- •Known hypersensitivity to alpha-L-iduronidase (IDUA/Aldurazyme) or any components/excipients found in AGT-181
- •Previous successful (engrafted) hematopoietic stem cell transplantation which has resulted in normalization of urinary glycosaminoglycans (GAGs); or major organ transplantation
- •Clinically significant spinal cord compression or evidence of cervical instability (i.e. expected to require intervention during study participation)
- •History of diabetes mellitus or hypoglycemia
- •Additional Exclusion Criteria, Stage 2:
- •Has ventriculoperitoneal shunt
- •IQ below 55
- •Previously received AGT-181 in Stage 1 of the study
研究组 & 干预措施
Stage 1 (adult)
AGT-181
干预措施: AGT-181 (Drug)
Stage 2 (children)
AGT-181
干预措施: AGT-181 (Drug)
结局指标
主要结局
Stage 1: number of patients with adverse events as a measure of safety and tolerability of a single dose
时间窗: 4 weeks
Stage 2: number of patients with adverse events as a measure of safety and tolerability of repeat weekly doses
时间窗: 26 weeks
次要结局
- change in liver and/or spleen volume (measured by MRI)(26 weeks)
- change in functional capacity (6-minute walk test) or lung function (forced vital capacity)(26 weeks)
- change in total urinary glycosaminoglycans (GAGs)(26 weeks)
- PK parameters (maximal concentration, half-life, AUC, distribution and clearance) of AGT-181(26 weeks)
- change in shoulder range of motion (ROM)(26 weeks)