A Phase 1/2/3 First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Efficacy of a Single Intravenous (IV) Administration of ECUR-506 in Males Less Than 9 Months of Age With Genetically Confirmed Neonatal Onset Ornithine Transcarbamylase (OTC) Deficiency
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- iECURE, Inc.
- 入组人数
- 20
- 试验地点
- 20
- 主要终点
- Physical exam parameters
研究概览
简要总结
Ornithine Transcarbamylase (OTC) deficiency, the most common urea cycle disorder, is an inherited metabolic disorder caused by a genetic defect in a liver enzyme responsible for detoxifying of ammonia. Individuals with OTC deficiency can develop elevated levels of ammonia in the blood, potentially resulting in severe consequences, including cumulative and irreversible neurological damage, coma, and death. The most severe form presents shortly after birth and occurs more commonly in boys than girls.
This is a Phase 1/2/3, open-label, multicenter study evaluating the safety, efficacy, and dose of ECUR-506 in male babies with neonatal-onset OTC deficiency. The primary objective is to evaluate the safety, tolerability, and efficacy of up to three dose levels of ECUR-506 following intravenous (IV) administration of a single dose.
详细描述
The study drug, ECUR-506, is an investigational gene editing therapy. Gene editing is an approach used to repair, replace, or introduce functional copies of genes that are not working properly. ECUR-506 contains a functional copy of the OTC gene, along with a gene to encode an editing enzyme that enables insertion of the OTC gene into the genome. The study drug is administered as a single IV infusion. Because genes cannot enter cells on their own, ECUR-506 uses a delivery system based on adeno-associated virus (AAV), a commonly used viral vector, to transport the genetic material into cells.
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
- 24 Hours 至 7 Months（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Gestational or adjusted (corrected) gestational age ≥ 37 weeks
- •Age at screening is 24 hours to 7 months
- •Weight ≥ 3.5 kg and ≤ 13.5 kg at screening
- •Has received age-appropriate vaccinations
- •Genetically confirmed OTCD defined by genetic confirmation of an OTC variant (pathogenic or likely pathogenic) associated with severe neonatal OTCD defined below in Inclusion Criteria #7 or has the same OTC variant as a family member who had severe neonatal OTCD within first week of life.
- •Severe neonatal OTCD defined by hyperammonemic crisis with elevated ammonia level of >560 μmol/L and clinical symptoms within first week of life, and currently receiving treatment with both dietary protein restriction and nitrogen scavenger therapy.
- •Current or historical biochemical profile consistent with OTCD
- •Participant's parent(s)/LAR must be able to comprehend and be willing to provide a signed IRB/IEC-approved ICF.
排除标准
- •Neonatal diagnosis of severe to profound Hypoxic Ischemic Encephalopathy due to birth injury
- •Requiring urgent liver transplant due to liver failure as assessed by the PI.
- •Contiguous gene deletion involving the OTC gene and including at least the CYBB gene on the telomeric side or the TSPAN7 gene on the centromeric side.
- •Known or suspected major organ injury/dysfunction/anomalies.
- •Vital sign and laboratory abnormalities outside of reference ranges.
- •Treatment with any other gene therapy or gene editing therapy
- •Co-enrollment in any other study unless approved by the sponsor.
- •Any condition, that in the opinion of the Investigator, would compromise the safety of the participant or study data
- •Documented vertical transmission of HepA/HepB/HepC
- •Documented in-utero teratogen, substance, and/or alcohol exposure, which in the opinion of the Investigator may increase the participant's risk of developmental delays, congenital anomalies, and/or significant medical complications
研究组 & 干预措施
Low Dose Level
Participants will receive the Low Dose of ECUR-506 delivered one time via IV Infusion.
干预措施: ECUR-506 (Genetic)
Intermediate Dose Level
Participants will receive an intermediate dose of ECUR-506 delivered on time via IV infusion
干预措施: ECUR-506 (Genetic)
High Dose Level
Participants will receive a higher dose of ECUR-506 delivered one time via IV infusion.
干预措施: ECUR-506 (Genetic)
结局指标
主要结局
Physical exam parameters
时间窗: Assessed as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Safety- (Includes PI assessment of General Appearance, Dermatological, HEENT, Lymphatic, Respiratory, Cardiovascular, Gastrointestinal, Musculoskeletal, Neurological (Cranial Nerve Function, Motor System Function, Sensory System Function, Primitive Reflexes))
Vital sign parameters
时间窗: Assessed as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Safety- (Includes PI assessment of Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, Respiratory Rate, Temperature)
Pediatric neurologist exam parameters
时间窗: Assessed as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Safety- (Includes Pediatric Neurologist assessment of Neurological status by review of Cranial Nerve Function, Motor System Function, Sensory System Function, Primitive Reflexes.)
Blood safety tests including hematology, serum chemistry, liver function tests, coagulation tests
时间窗: as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Safety- (Blood Safety tests to be reviewed in relation to established normal ranges for each assessment for the applicable age group)
12 lead ECG parameters
时间窗: as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Safety- (Includes PI review of Heart Rate, PR Interval, RR Interval, QRS Duration, QT Interval, QTcF Interval, Overall Interpretation)
Treatment-emergent adverse events (incidence, severity, seriousness, and relatedness)
时间窗: Over 24 weeks post infusion
Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse events (AEs) are reported based on clinical laboratory tests, vital signs, physical examinations, Pediatric Neurologist exam parameters, electrocardiograms, and any other medically indicated assessments from the time informed consent is signed through the end of the safety follow-up period. AEs are considered to be treatment emergent (TEAE) if they occur or worsen in severity following the administration of the study treatment. TEAEs are considered treatment-related if relationship to study drug is possibly related, probably related, or definitely related.
Urinalysis evaluations
时间窗: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse events (AEs) are reported based on clinical laboratory tests, vital signs, physical examinations, electrocardiograms, and any other medically indicated assessments from the time informed consent is signed through the end of the safety follow-up period. AEs are considered to be treatment emergent (TEAE) if they occur or worsen in severity following the administration of the study treatment. TEAEs are considered treatment-related if relationship to study drug is possibly related, probably related, or definitely related.
Achieving normal fasting plasma ammonia levels by EOS
时间窗: Over 24 weeks post infusion
Fasting plasma ammonia levels that fall within normal limits for at least 75% of post-dose assessments.
Complete clinical response
时间窗: Over 24 weeks post infusion
Discontinuation of scavenger medication for a minimum duration of 28 days without reductions in prescribed daily protein intake during this time period by end of study.
次要结局
- Number of HAEs/person-year(Day 1 post dose through Week 24)
- Incidence of hyperammonemic episode (HAE)(Over 24 weeks post infusion)
- Incidence and number of hyperammonemic episodes (HAE/HAC) resulting in hospitalization(Over 24 weeks post infusion)
- Overall and by hospitalization severity (Mild: adjustment of dietary protein intake and oral scavenger medication / Moderate: cessation of dietary protein intake and initiation of IV scavenger therapy / Severe: requirement for hemodialysis)(Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants)
- Duration of hospitalization for each HAE/HAC(Over 24 weeks post infusion)
- Requirement for Intensive Care Unit (ICU) care during hospitalization for each HAE/HAC(Over 24 weeks post infusion)
- Time to liver transplant from dosing to end of study (EOS)(Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.)
- Transplant free survival(Time to lever transplant or any-cause death from dosing to EOS)
- Overall survival(Time to any-cause death from dosing to EOS)
- Achieving and maintaining complete clinical response through end of study(Over 24 weeks post infusion)
- Scavenger drug dose(Over 24 weeks post infusion)
- Dietary protein intake g/kg/day(Supportive Secondary: Over 24 weeks post infusion)
- Scavenger drug dose per body surface area (BSA)(Over 24 weeks post infusion)
- Protein allowance g/kg/day(Over 24 weeks post infusion)
- Percent liver transduction(Assessed at Week 24)
- Number of hyperammonemic crises (HAC)(Over 24 weeks post infusion)
- qPCR measurement to evaluate the clearance of both vectors in body fluids over time(Over 24 weeks post infusion)
- Blood urea nitrogen measurements(Over 24 weeks post infusion)
- Fasting plasma ammonia(Over 24 weeks post infusion)