An Investigator-Initiated Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of RC001 in Patients With Dravet Syndrome Aged 2 to 18 Years
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Number of Participants With Clinically Significant Abnormal 12-Lead Electrocardiogram (ECG) Findings
研究概览
简要总结
This is an open-label, single-center study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of intrathecal RC001 in patients with Dravet syndrome aged 2 to 18 years. The study includes a dose-escalation part followed by a fixed dose treatment part, with participant progression based on investigator-assessed safety and efficacy.
详细描述
This is an open-label, single-center clinical study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of RC001 administered intrathecally in patients aged 2 to 18 years with Dravet syndrome. The study consists of two stages: Stage 1 (intra-subject dose escalation) and Stage 2 (fixed-dose multiple dosing). In Stage 1, three cohorts will be enrolled with a total of three participants. In Stage 2, a total of five participants will be enrolled to receive fixed-dose multiple administrations. Participants in both the dose-escalation stage and the fixed-dose multiple dosing stage may enter an extension phase after completion of the last dose, based on the investigator's assessment of efficacy and safety.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This is an open-label study; no parties are masked.
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 aged 2-18 years with Dravet syndrome caused by SCN1A mutations, with onset before 12 months of age characterized by focal seizures, hemiclonic seizures, generalized tonic-clonic seizures, or myoclonic seizures, and with MRI excluding progressive neurological disease either historically or at screening. Enrolled participants will be assigned as follows: 1 participant aged 13-18 years, 1 aged 7-12 years, and 1 aged 2-6 years will undergo intra-subject dose escalation; 5 participants aged 2-12 years will receive fixed-dose multiple administrations.
- •Seizure frequency requirements: at least 6 cumulative seizures within 12 weeks prior to the day of signing the ICF, and at least 2 seizures within 4 weeks prior to ICF signing. For participants in Stage 2 (fixed-dose multiple administration), seizure frequency must also be ≥4 within 4 weeks after ICF signing.
- •Documented pathogenic or likely pathogenic variants in the SCN1A gene associated with Dravet syndrome.
- •Prior treatment with at least one anti-epileptic intervention, including anti-seizure medications (ASM), ketogenic diet, or vagus nerve stimulation (VNS), with inadequate seizure control or discontinuation due to adverse events (AEs).
- •Use of at least one ASM prior to screening, with a stable dose for at least 4 weeks before screening.
- •All epilepsy-related treatments, including ASM and other interventions (ketogenic diet and VNS), must be stable for at least 4 weeks prior to screening and are expected to remain stable throughout the study (medications adjusted by body weight are allowed).
- •Willingness to participate and provision of written informed consent.
排除标准
- •Presence of other known pathogenic gene mutations causing Dravet syndrome, or SCN1A gain-of-function mutations reported in the literature and/or experimentally validated, including but not limited to: Ala23Glu, Thr162Ile, Thr226Met, Ser228Pro, Val229Leu, Ile236Val, Ile236Thr, Val250Leu, Leu263Val, Thr398Met, Ala420Val, Val422Leu, Ile883Thr, Leu893Phe, Ala989Thr, Thr1174Ser, Trp1204Arg, Ala1339Asp, Pro1345Ser, Pro1345Leu, Ser1346Pro, Ile1347Val, Val1481Ile, Ile1483Met, Gln1489Lys, Ile1498Thr, Ile1498Met, Phe1499Leu, Met1500Val, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1636Gln, Arg1648Cys, Leu1649Gln, Leu1660Ile, Phe1661Leu, Ala1669Glu, Leu1670Trp, Gly1674Arg, Phe1774Ser, Asp1866Tyr.
- •Current maintenance treatment with anti-epileptic drugs primarily acting as sodium channel blockers, including but not limited to carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide.
- •Ongoing neuromodulation therapy (e.g., responsive neurostimulation or deep brain stimulation), excluding vagus nerve stimulation (VNS).
- •Receipt of gene therapy or cell therapy within 1 year prior to screening.
- •Receipt of any vaccination within 12 weeks prior to screening.
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2× the upper limit of normal (ULN), or total bilirubin >1.5× ULN; renal insufficiency or serum creatinine >1.2× ULN.
- •Presence of any severe uncontrolled disease other than Dravet syndrome.
- •History of autoimmune disease, or uncontrolled infectious disease within 1 week prior to screening.
- •History of brain or spinal cord disease (other than epilepsy, Dravet syndrome, or trauma), or history of bacterial meningitis.
- •Spinal deformity or other conditions that may interfere with normal cerebrospinal fluid (CSF) flow, or implantation of a CSF shunt.
- •Pregnant or breastfeeding females.
- •Any other significant disease or condition that, in the investigator's judgment, may pose a risk to the patient, interfere with study results, or affect the patient's ability to participate in the study.
结局指标
主要结局
Number of Participants With Clinically Significant Abnormal 12-Lead Electrocardiogram (ECG) Findings
时间窗: From baseline to 24 weeks after the last dose
ECG parameters may include heart rate, PR interval, QRS duration, QT interval, and corrected QT interval. Clinically significant abnormalities will be determined by the investigator.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: From first dose to 24 weeks after the last dose
A treatment-emergent adverse event is defined as any adverse event that occurs or worsens after the first dose of RC001 through the end of follow-up. TEAEs will be summarized by system organ class, preferred term, severity, seriousness, and relationship to study drug or study procedure.
Number of Participants With Serious Adverse Events (SAEs)
时间窗: From signing informed consent to 24 weeks after the last dose
Serious adverse events will be collected and summarized throughout the study.
Number of Participants With Clinically Significant Abnormalities in Vital Signs
时间窗: From baseline to 24 weeks after the last dose
Vital signs include body temperature, heart rate, respiratory rate, systolic blood pressure, and diastolic blood pressure. Clinically significant abnormalities will be determined by the investigator.
Number of Participants With Clinically Significant Abnormal Physical Examination Findings
时间窗: From baseline to 24 weeks after the last dose
Physical examination findings will be assessed for clinically significant abnormalities as determined by the investigator.
Number of Participants With Clinically Significant Abnormal Laboratory Test Results
时间窗: From baseline to 24 weeks after the last dose
Laboratory assessments may include hematology, serum chemistry, coagulation, urinalysis, and cerebrospinal fluid laboratory tests, as applicable. Clinically significant abnormalities will be determined by the investigator.
次要结局
- Maximum Observed Plasma Concentration (Cmax) of RC001(From first dose to last dose up to 12 weeks)
- Time to Maximum Observed Plasma Concentration (Tmax) of RC001(From first dose through 12 weeks)
- Trough Concentration (Ctrough) of RC001 in Cerebrospinal Fluid(Prior to each dose through 12 weeks)
- Percentage Change From Baseline in Countable Seizure Frequency at 12 Weeks After the Last Dose(Baseline and the 28-day period preceding 12 weeks after the last dose)
- Percentage Change From Baseline in Countable Seizure Frequency at 24 Weeks After the Last Dose(Baseline and the 28-day period preceding 24 weeks after the last dose)
- Clinical Global Impression of Change (CGI-C) Score at 24 Weeks After the Last Dose(24 weeks after the last dose)
- Caregiver Global Impression of Change (CaGI-C) Score at 24 Weeks After the Last Dose(24 weeks after the last dose)
- Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Expressive Communication Raw Score at 24 Weeks After the Last Dose(Baseline and 24 weeks after the last dose)
- Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Receptive Communication Raw Score at 24 Weeks After the Last Dose(Baseline and 24 weeks after the last dose)
- Change From Baseline in Age-Appropriate Wechsler Intelligence Scale Score at 24 Weeks After the Last Dose(Baseline and 24 weeks after the last dose)