A Phase 2, Two-Stage, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of RLS-0071 in Newborns With Moderate or Severe Hypoxic-Ischemic Encephalopathy Undergoing Therapeutic Hypothermia With Long-Term Follow-Up
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 30
- 主要终点
- Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment group at Day 14
研究概览
简要总结
Hypoxic-ischemic encephalopathy (HIE) affects approximately 4,000 to 12,000 persons annually in the United States. Mortality from HIE has been reported up to 60%, with at least 25% of survivors left with significant neurocognitive disability. Despite this vital unmet medical need, no pharmacological adjunct or alternative therapy has proven beneficial in improving outcomes in neonatal HIE.
RLS-0071 is a novel peptide being developed for the treatment of neonatal HIE. This study is designed to evaluate the safety and tolerability of RLS-0071 in the treatment of newborns with moderate or severe HIE.
详细描述
This is a Phase 2, two-stage, multisite, randomized, double-blind, placebo-controlled, multiple-ascending dose study of RLS-0071 to assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy in newborns with moderate or severe HIE undergoing therapeutic hypothermia.
In Stage 1, participants will receive either ascending doses of RLS-0071 or a matched volume of placebo for 72 hours in addition to standard of care treatment, including therapeutic hypothermia. During and after the dosing period, participants will be monitored and assessed for safety evaluations through Day 14. After completion of Stage 1, participants will transition to Stage 2 of the study for long-term observation until participants reach 24 months of age.
The first cohort subsets, consisting of Cohort 1a (moderate HIE) and 1b (severe HIE), will receive a dose of 3 mg/kg RLS-0071 or a matched volume of placebo every 8 hours (q8h). A Data Safety Monitoring Board (DSMB) will review available clinical safety and PK data from Cohort 1 subsets with completed study intervention, and make a recommendation on whether to escalate the dose for moderate and severe HIE cohorts. The Sponsor will consider the DSMB recommendation to make their decision on dose escalation in addition to their own evaluation of all available safety and PK data. If the decision is made to escalate, Cohort 2 subsets (2a [moderate] and 2b [severe]) will be recruited to receive an escalated dose of RLS-0071 (10 mg/kg) or a matched volume of placebo. Following the completion of study intervention for each Cohort 2 subset (2a [moderate] or 2b [severe]), the DSMB will review available safety and PK data and make a recommendation whether to expand enrollment for Cohort 2+ (2a+ [moderate] or 2b+ [severe]) at 10 mg/kg RLS-0071 or a matched volume of placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The blinded study team members (eg, Investigators and study staff) and participants' parent(s)/legal guardian(s) will be blinded to treatment group assignments throughout the study.
入排标准
- 年龄范围
- — 至 10 Hours（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≥ 36 weeks gestation.
- •Sentinel event prior to delivery such as abruption, tight nuchal cord, uterine rupture, profound bradycardia, shoulder dystocia, or cord prolapse or other acute event likely attributable for newborn depression at delivery or an acute change in the fetal status with a clinical presentation consistent with an acute sentinel event with no clearly defined etiology.
- •Moderate or severe encephalopathy based on at least one risk of encephalopathy criterion (a) and one clinical signs of encephalopathy criterion (b):
- •Risk of encephalopathy (either):
- •Blood gas drawn within 1 hour of birth, either arterial blood gas (ABG) or venous blood gas (VBG) (cord or infant) with pH ≤ 7.0 OR base deficit ≥ 16 mmol/L.
- •appearance, pulse, grimace, activity, and respiration (APGAR) score ≤ 5 at 10 minutes OR
- •The infant required assisted ventilation ≥ 10 minutes after birth (ie, endotracheal, mask ventilation, or continuous positive airway pressure [CPAP]).
- •Clinical signs of encephalopathy (either/both):
- •Moderate/Severe encephalopathy on National Institute of Child Health and Human Development assessment.
- •Evidence of seizures (clinical and/or electroencephalogram).
- •Be eligible to receive therapeutic hypothermia.
- •Active whole-body cooling to be started prior to 6 hours of age (passive cooling is permitted prior to active whole body cooling).
- •Product of a singleton pregnancy.
- •Written informed consent obtained from parent or legal guardian.
排除标准
- •Inability to enroll in the study and initiate the first dose of RLS-0071 within 10 hours of life.
- •Known major congenital and/or chromosomal abnormality(ies).
- •Severe growth restriction (birth weight ≤ 1800 g).
- •Prenatal diagnosis of brain abnormality or hydrocephalus.
- •Patient's head circumference is < 30 cm.
- •10-minute APGAR score < 2, if available.
- •Infants suspected of overwhelming sepsis or congenital infection based on the Investigator's clinical consideration at the time of enrollment.
- •Persistent severe hypotension unresponsive to inotropic support (requiring >2 inotropes, not inclusive of hydrocortisone).
- •Persistent severe hypoxia in the setting of 100% fraction of inspired oxygen (FiO₂) and unresponsive to nitric oxide or requiring extracorporeal membrane oxygenation (ECMO).
- •Severe disseminated intravascular coagulation with clinical bleeding.
- •Neonatal encephalopathy believed to be due to a cause other than perinatal hypoxia (ie, other than HIE).
- •Moribund infants for whom withdrawal of care being considered.
- •Suspected or confirmed fetal alcohol syndrome or suspected substance withdraw seizures.
- •Any other condition that the investigator may consider would make the patient ineligible for the study or place the patient at an unacceptable risk (Note: this criterion would include a clinically significant [eg, Grade 3 or 4] intracranial hemorrhage).
研究组 & 干预措施
RLS-0071
Doses of RLS-0071 to be administered every 8 hours (q8h), for a total of 10 doses over 72 hours.
干预措施: RLS-0071 (Drug)
Placebo
Doses of sterile saline (sodium chloride, 0.9%) to be administered every 8 hours (q8h), for a total of 10 doses over 72 hours.
干预措施: Placebo (Drug)
结局指标
主要结局
Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment group at Day 14
时间窗: Day 1 to Day 14
Number of participants with AEs and SAEs graded between Grade 1 (mild in severity) and Grade 5 (death related to AE).
Frequency and severity of events of special interest and SAEs by treatment group at 24 months
时间窗: Day 1 to 24 months
Number of participants with events of special interest and SAEs graded between Grade 1 (mild in severity) and Grade 5 (death related to AE). Events of special interest are: autoimmune disorder, persistent hypotension, persistent pulmonary hypertension, acute kidney injury, major venous thrombosis, severe intracranial hemorrhage, pulmonary hemorrhage, culture proven sepsis, necrotizing enterocolitis, severe thrombocytopenia, hepatic dysfunction, hyperbilirubinemia, coagulopathy, hypocalcemia, cerebral palsy, developmental or speech delay, learning disability, and visual or hearing impairment.
Frequency of premature discontinuation by treatment group due to AEs at Day 14
时间窗: Day 1 to Day 14
Number of participants who prematurely discontinue from the study due to AEs
Acute brain injury at Day 4, assessed through magnetic resonance imaging (MRI), using a standardized scoring system
时间窗: Day 4
Brain injury MRI score includes scoring extent of injury across 4 domains (Grey matter, White matter/cortex, Cerebellum, and Additional). A score of 0 indicates a normal brain MRI, whereas the maximum score of 57 indicates extensive bilateral injury.
Acute brain injury at Day 12, assessed through magnetic resonance imaging (MRI), using a standardized scoring system
时间窗: Day 12
Brain injury MRI score includes scoring extent of injury across 4 domains (Grey matter, White matter/cortex, Cerebellum, and Additional). A score of 0 indicates a normal brain MRI, whereas the maximum score of 57 indicates extensive bilateral injury.
次要结局
- Neurodevelopmental growth impact: Diagnosis of cerebral palsy at 24 months of age(24 months)
- Neurodevelopmental growth impact: Grading of cerebral palsy by using the Gross Motor Function Classification System-Expanded and Revised (GMFCS-E&R) at 24 months of age(24 months)
- Number of participants diagnosed with mild, moderate, or severe visual impairment and hearing impairment(Day 1 to 24 months)
- Number of days of supplemental nutritional support required(Day 1 to 24 months)
- Seizure occurrence(Day 1 to Day 14)
- Total seizure burden (total number of minutes seizing as measured by continuous electroencephalogram [EEG]) during hospitalization(Day 1 to Day 14)
- Electrical activity abnormality scoring as measured by EEG(Day 1 to Day 14)
- Composite of mortality and neurodevelopmental impairment (NDI) at 24 months(Day 1 to 24 months)
- Mortality at 3, 6, 12, 18, and 24 months(Day 1 to 3, 6, 12, 18, and 24 months)
- Number of participants with clinically significant laboratory abnormalities, events of special interest, and SAEs at 3, 6, 12, and 18 months(Day 1 to 3, 6, 12, and 18 months)
- Neurocognitive developmental outcome assessed by Bayley-4 at 24 months of age(24 months)
- Impact on infant and family wellness, assessed by the Mother-to-Infant Bonding Scale (MIBS)(3 and 12 months)
- Impact on infant and family wellness, assessed by the Parenting Stress Index, 4th Edition Short Form (PSI-4-SF)(3, 12, and 24 months)
- Quality of life assessment over the first 24 months of life(Day 4 to 24 months)