A Phase 1/2/3 Open-label, Single Arm, Dose-finding Study to Investigate Long-term Safety, Tolerability and Efficacy of GS-100, an Adeno-associated Virus Serotype 9 (AAV9) Vector-mediated Gene Transfer of Human NGLY1, in Patients With NGLY1 Deficiency
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 10
- 试验地点
- 5
- 主要终点
- Coagulation as measured by prothrombin time (PT)
研究概览
简要总结
A non-randomized, open-label, Phase 1/2/3 study of a single intracerebroventricular (ICV) administration of a gene replacement therapy (GS-100) in participants who are 2 to 18 years old with NGLY1 Deficiency.
详细描述
This study is a first in human (FIH) open-label study designed to assess the safety and efficacy of administration of an adeno-associated viral vector serotype 9 (AAV9) carrying the gene encoding N-glycanase 1 (NGLY1) in subjects ages 2-18 years old with NGLY1 Deficiency. The study treatment is delivered via intracerebroventricular (ICV) injection.
Phase 1/2 is the open-label dose finding part of the study designed to evaluate the safety and preliminary efficacy of GS-100 at 4 different dose levels and to select a safe and efficacious dose for the Phase 3 part of the study. Enrollment of 7 participants in the Phase 1/2 part of the study is complete.
Phase 3 is evaluating the efficacy and safety of GS-100 at the Selected Dose determined in the Phase 1/2 part of the study (Mid dose: 1e15 for 6-18-year-olds, 8.7e14 for 2-5-year-olds). Enrollment of 3 participants in the Phase 3 part of the study is complete.
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 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must be 2 to 18 years of age, inclusive, at the time of signing the informed consent form (ICF)
- •Patients with a documented diagnosis of NGLY1 Deficiency based on detection of biallelic variants in the NGLY1 gene via molecular genetic sequencing
- •Elevated GNA levels may be considered alongside genetic sequencing data and other clinical data to assist with diagnosis confirmation
- •Patients with two or more of the following clinical features typical of NGLY1 Deficiency:
- •Global developmental delay and/or intellectual disability
- •Hyperkinetic movement disorder
- •Transient elevation of transaminases
- •(Hypo)alacrima
- •Peripheral neuropathy
- •For patients with epilepsy who require anti-seizure medications for seizure control: must be on a stable regimen for 28 days prior to enrollment
- •Patients willing and capable per investigator opinion to comply with study procedures and requirements
- •Females of childbearing potential must have a negative serum pregnancy test at screening and must agree to use an acceptable method of highly effective contraception from screening through the end of the study
- •Patients or parent(s)/guardian(s) must be willing and able to provide written consent after the nature of the study has been explained and prior to performance of any research-related procedures
排除标准
- •For Phase 1/2 only: Patients at Level 5 of both the Gross Motor Function Classification System Expanded and Revised (GMFCS E&R) and the Communication Function Classification System (CFCS) scales as assessed by the investigator
- •Contraindication to use of corticosteroids or history of a condition that could worsen with corticosteroid therapy, as assessed, and determined by the investigator
- •Signs / symptoms of increased intracranial pressure (ICP), history of space occupying lesion, or ventricular shunt that would preclude ICV procedures or safety assessments
- •a. If clinical signs or symptoms of increased ICP are present (such as headache, vomiting, altered mental status), an ophthalmology examination will be performed to assess for papilledema and/or venous pulsations
- •Any comorbid medical or behavioral condition that, in the opinion of the investigator, may adversely affect the safety and well-being of the participant during the study, interfere with completion of the study procedures or follow-up, or compound interpretation of the study results
- •Vital signs outside age-based normative values:
- •Blood pressure: values > 99th percentile as cited in the National Heart, Lung and Blood Institute (NHLBI) guidelines for blood pressure levels based on subject's age, height and sex (nhlbi.nih.gov/files/docs/guidelines/child_tbl.pdf)
- •Temperature: evidence of fever such as body temperature (e.g., orally measured) of 38.0°C (100.3°F)
- •Respiratory rate in breaths per minute: toddler (1-3 years old): 24-40; preschooler (4-5 years old): 22-34 breaths per minute; school-aged child (6-12 years old): 18-30 breaths per minute; adolescence (13-18 years old): 12-
- •Oxygen saturation on room air < 92%
- •Any condition that in the opinion of the investigator or the study medical monitor would prevent the patient from fully complying with the requirements of the study (including the corticosteroid treatment outline in the protocol) and/or would impact or interfere with the evaluation and interpretation of patient safety or efficacy results
- •Known allergy or hypersensitivity to the GS-100 investigational product formulation
- •Prior treatment with gene therapy
- •Treatment with any investigational product (IP) within 30 days or 5 half-lives of the IP, whichever is longer, prior to screening period. For patients who have received a prior investigational product, all ongoing AEs experienced while receiving the investigational product must have been resolved prior to screening for this study
- •Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study that does not interfere with the requirements of the current protocol and does not have the potential to impact the evaluation of safety and efficacy of GS-100
- •Coagulation dysfunction at screening as defined by the following:
- •a. INR: ≥1.4 x Upper Limit of Normal (ULN)
- •Any current infection with hepatitis B virus (HBV) as evidenced by as evidenced by positive HBV surface antigen (HBsAg), and/or HBV core antibody (HBcAb) at screening. Isolated HBsAb positivity for HBV vaccination in conjunction with negative confirmatory HBV DNA testing at screening is not exclusionary
- •Any prior or current infection with hepatitis C virus (HCV) as evidenced by positive HCV antibody testing and confirmed by positive polymerase chain reaction (PCR) RNA testing at screening
- •Any of the following abnormal laboratory values:
- •Hemoglobin level: < 9 g/dL
- •Absolute neutrophil count: < 1000 cells/microliter
- •Platelet count: < 100,000/mm3
- •Creatinine: > 1.25 x ULN
- •Have a major surgery planned during the screening period through 52 weeks following GS-100 infusion, including major dental procedures (e.g., wisdom tooth extraction)
- •Pregnant or breastfeeding female patient
- •Patients that demonstrate elevated serum adrenocorticotropic hormone (ACTH) 1.5 times the upper limit of normal for the reference range must be referred for consultation with a pediatric endocrinologist to rule out primary adrenal insufficiency prior to being enrolled into the study. Patients may re-screen for participation in the study after medical consultation and / or possible treatment has been initiated to address any adrenal insufficiency
研究组 & 干预措施
Cohort 2
GS-100 Mid Dose Level: 1e15 total vector genomes (vg) for 13-18-year-olds, 8.7e14 total vg for 2-5-year-olds (fully enrolled, 2 participants)
干预措施: GS-100 (Genetic)
Cohort 3
GS-100 High Dose Level: 3e15 total vector genomes (vg) for 6-18-year-olds, 2.6e15 vg for 2-5-year-olds (fully enrolled, 2 participants)
干预措施: GS-100 (Genetic)
Cohort 1
GS-100 Low Dose Level: 4e14 total vector genomes (vg) for 6-18-year-olds (fully enrolled, 2 participants)
干预措施: GS-100 (Genetic)
Cohort 4
GS-100 Intermediate Dose Level: 2e15 total vector genomes (vg) for 6-18-year-olds, 1.75e15 total vg for 2-5-year-olds (fully enrolled, 1 participant)
干预措施: GS-100 (Genetic)
Pivotal Cohort
GS-100 Selected Dose Level: 1e15 total vector genomes (vg) for 6-18-year-olds, 8.7e14 total vg for 2-5-year-olds (fully enrolled, 3 participants)
干预措施: GS-100 (Genetic)
结局指标
主要结局
Coagulation as measured by prothrombin time (PT)
时间窗: 5 years (multiple visits)
Alkaline phosphatase (ALP)
时间窗: 5 years (multiple visits)
Sodium (meq/L)
时间窗: 5 years (multiple visits)
Chloride (meq/L)
时间窗: 5 years (multiple visits)
Bicarbonate (meq/L)
时间窗: 5 years (multiple visits)
Change in liver size by palpation
时间窗: 5 years (multiple visits)
Complete blood count (CBC)
时间窗: 5 years (multiple visits)
Partial prothrombin time (aPTT)
时间窗: 5 years (multiple visits)
To assess for inflammation or evidence of microgliosis or astrocytosis on MRI
时间窗: 5 years (multiple visits)
Change in cardiac size as assessed by chamber size and wall thickness on echocardiogram
时间窗: 5 years (multiple visits)
Creatinine (mg/dL)
时间窗: 5 years (multiple visits)
Albumin (g/dL)
时间窗: 5 years (multiple visits)
Total bilirubin (mg/dL)
时间窗: 5 years (multiple visits)
Alkaline phosphatase (U/L)
时间窗: 5 years (multiple visits)
Incidence of adverse events (AEs) and serious AEs (SAEs)
时间窗: 5 years (multiple visits)
International normalized ratio (INR)
时间窗: 5 years (multiple visits)
Alanine aminotransferase (ALT)
时间窗: 5 years (multiple visits)
Potassium (meq/L)
时间窗: 5 years (multiple visits)
Direct bilirubin (mg/dL)
时间窗: 5 years (multiple visits)
Calcium (mg/dL)
时间窗: 5 years (multiple visits)
Phosphate (mg/dL)
时间窗: 5 years (multiple visits)
Gamma-glutamyl transferase (GGT)
时间窗: 5 years (multiple visits)
Serum troponins
时间窗: 5 years (multiple visits)
Change in nerve conduction velocity (NCV) as assessed by nerve conduction studies
时间窗: 5 years (multiple visits)
Change in cardiac function as assessed by ejection fraction on echocardiogram
时间窗: 5 years (multiple visits)
Blood urea nitrogen (BUN) (mg/dL)
时间窗: 5 years (multiple visits)
Glucose (mg/dL)
时间窗: 5 years (multiple visits)
Total protein (g/dL)
时间窗: 5 years (multiple visits)
Lactic dehydrogenase (U/L)
时间窗: 5 years (multiple visits)
Phase 1/2 (Dose Finding): Safety and Tolerability of GS-100
时间窗: Baseline through Week 52
Incidence of adverse events (AEs) and serious AEs (SAEs)
Phase 3 (Pivotal): Efficacy of GS-100 at the Selected Dose
时间窗: Baseline through Week 52
Improvement in one or more domains of the 88-item Gross Motor Function Measure (GMFM-88) from Baseline to Week 52
次要结局
- Change from baseline at 52 weeks in Clinical Global Impression of Change (CGI-C)(52 weeks)
- Detection of antibodies against AAV9 capsid (AAV9 Total antibodies, AAV9 Neutralizing antibodies) and NGLY1 (NGLY1 Total antibodies)(5 years (multiple visits))
- Change from baseline at 52 weeks in sitting/standing assessment at 52 weeks(52 weeks)
- Change from baseline at 52 weeks in Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV)(52 weeks)
- Change from baseline at 52 weeks in Caregiver Global Impression of Severity (CaGI-S)(52 weeks)
- Change from baseline at 52 weeks in peripheral nerve function measured by nerve conduction velocity (NCV) in msecs(52 weeks)
- Change from baseline at 52 weeks in Vineland Adaptive Behavior Scales-3 assessment (Vineland-3) for the Communication, Daily Living skills, Socialization, and Motor domains(52 weeks)
- Change from baseline of GNA (GlcNAc-Asn, or N-acetylglucosamine) level in CSF(5 years (multiple visits))
- Assessment of NGLY1 and capsid-specific cellular immunity by enzyme-linked immunosorbent spot (ELISpot) on peripheral blood mononuclear cells (PBMC)(5 years (multiple visits))
- Change from baseline at 52 weeks in weight (Z-score)(52 weeks)
- Change from baseline at 52 weeks in Pediatric Quality of Life Inventory (PedsQL)(52 weeks)
- Change from baseline at 52 weeks in Clinical Global Impression of Severity (CGI-S)(52 weeks)
- Change from baseline at 52 weeks in Bayley Scales of Infant and Toddler Development 4th Ed (BSID-4) for the Cognitive, Language, and Motor scales(52 weeks)
- Change from baseline at 52 weeks in Gross Motor Function Measure (GMFM)(52 weeks)
- Change from baseline at 52 weeks in seizure frequency in subjects with seizures(52 weeks)
- Individual domains of the Bayley Scales of Infant and Toddler Development 4th Ed (BSID-4) for the Cognitive, Language, and Motor scales(Baseline through Week 52)
- Clinical Global Impression of Change (CGI-C)(Baseline through Week 52)
- Clinical Global Impression of Severity (CGI-S)(Baseline through Week 52)
- Videotaped movement disorder assessments(Baseline through Week 52)
- Sitting/standing assessment(Baseline through Week 52)
- Failure to thrive(Baseline through Week 52)
- Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV)(Baseline through Week 52)
- Caregiver Global Impression of Change (CaGI-C)(Baseline through Week 52)
- Caregiver Global Impression of Severity (CaGI-S)(Baseline through Week 52)
- Nerve conduction velocity (NCV)(Baseline through Week 52)
- Seizure frequency in subjects with seizures(Baseline through Week 52)