An Open-Label Adaptive-Design Study of Intracisternal Adenoassociated Viral Vector Serotype rh.10 Carrying the Human β-Galactosidase cDNA for Treatment of GM1 Gangliosidosis
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- LYSOGENE
- 入组人数
- 5
- 试验地点
- 6
- 主要终点
- Stage 1: Vital signs: change from baseline in body temperature
研究概览
简要总结
LYS-GM101 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the central nervous system. This study will assess, in a 2-stage adaptive-design, the safety and efficacy of treatment in subjects with infantile GM1 gangliosidosis.
详细描述
GM1 gangliosidosis is a fatal autosomal recessive disease caused by mutations in the GLB1 gene leading to accumulation of GM1 ganglioside in neurons and progressive neurodegeneration. There are three pediatric subtypes: early infantile, late infantile and juvenile. This is an interventional, multicenter, single-arm, 2-stage adaptive design study of LYS-GM101 for which the first stage (Stage 1) is for safety evaluation (FIH) and the second stage (Stage 2) will establish efficacy as compared to the natural history of the disease. The participants with infantile GM1 gangliosidosis will receive a single dose of LYS-GM101 by intracisternal injection. After a two-year evaluation period (main part of the study), each participant will be followed for an additional three-year long-term follow-up period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 3 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented GM1 gangliosidosis diagnosis based on genotyping confirming the β-gal gene mutations and/or documented deficiency of β-gal enzyme by laboratory testing
- •Children with early infantile GM1 gangliosidosis less than 12 months of age with ability to swallow
- •Children with late infantile GM1 gangliosidosis less than 3 years of age with ability to sit
排除标准
- •Uncontrolled seizure disorder. Patients who are stable on anti-convulsive medications may be included
- •More than 40% brain atrophy as measured by MRI total brain volume at screening
- •Current participation in a clinical trial of another investigational medicinal product
- •Past participation in a gene therapy trial
- •History of hematopoietic stem cell transplantation
- •Any condition that would contraindicate treatment with immunosuppressant therapy
- •Presence of concomitant medical condition or anatomical abnormality precluding lumbar puncture or intracisternal injection
- •Presence of any permanent items (e.g., metal braces) precluding undergoing MRI
- •History of non-GM1 gangliosidosis medical condition that would confound scientific rigor or interpretation of results
- •Rare and unrelated serious comorbidities, e.g., Down syndrome, intraventricular hemorrhage in the new-born period, extreme low birth weight (<1500 grams) or known bleeding disorders
- •Any vaccination 1 month prior to the planned immunosuppressant treatment
- •Serology consistent with HIV exposure or consistent with active hepatitis B or C infection
- •Grade 2 or higher lab abnormalities for Liver function tests (LFT), bilirubin, creatinine, hemoglobin, white blood cell (WBC) count, platelet count, prothrombin time (PT), and partial thromboplastin time (PTT), according to CTCAE v5.0
结局指标
主要结局
Stage 1: Vital signs: change from baseline in body temperature
时间窗: Up to 6 months (multiple visits)
Vital signs: change from baseline in body temperature
Stage 1: Vital signs: change from baseline in diastolic and systolic blood pressure
时间窗: Up to 6 months (multiple visits)
Vital signs: change from baseline in diastolic and systolic blood pressure
Stage 1: Physical examination by body system
时间窗: Up to 6 months (multiple visits)
Physical examination by body system: normal/abnormal and change from previous assessment
Stage 1: Incidence of treatment-emergent adverse event and serious adverse events
时间窗: Up to 6 months (multiple visits)
Incidence of treatment-emergent adverse event and serious adverse events
Stage 1: Imaging: presence of bleeding post-administration
时间窗: Up to 6 months (multiple visits)
Imaging: presence of bleeding post-administration
Stage 1: Neurological examination
时间窗: Up to 6 months (multiple visits)
Neurological examination: normal/abnormal motor activity and coordination, and change from previous assessment
Stage 1: Vital signs: change from baseline in heart rate
时间窗: Up to 6 months (multiple visits)
Vital signs: change from baseline in heart rate
Stage 1: Change from baseline in biochemistry laboratory parameters
时间窗: Up to 6 months (multiple visits)
Change from baseline in biochemistry laboratory parameters
Stage 1: Change from baseline in coagulation and hematology laboratory parameters
时间窗: Up to 6 months (multiple visits)
Change from baseline in coagulation and hematology laboratory parameters
Stage 1: Assessment of humoral immune response by measurement of antibodies anti-AAV and anti-beta-galactosidase (ELISA) and cellular immune response by beta-galactosidase-specific T-cell proliferation assay
时间窗: Up to 6 months (multiple visits)
Assessment of humoral immune response by measurement of antibodies anti-AAV and anti-beta-galactosidase (ELISA) and cellular immune response by beta-galactosidase-specific T-cell proliferation assay
次要结局
- Motor Function(Up to 2 years (multiple visits))
- Blood and cerebrospinal fluid (CSF) biomarkers (beta-galactosidase)(Up to 2 years (multiple visits))
- Brain MRI(Up to 2 years (multiple visits))
- Developmental changes (VABS-II)(Up to 2 years (multiple visits))
- Developmental changes (BSID-III or KABC-II)(Up to 2 years (multiple visits))
- Blood and cerebrospinal fluid (CSF) biomarkers (GM1 ganglioside)(Up to 2 years (multiple visits))