An Open-label, Dose-escalation, Phase I/Ib Clinical Trial to Assess the Safety and Pharmacokinetics of Clemastine in Preterm Neonates With White Matter Injury (WRAP)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Number of subjects who experience dose limiting toxicity
研究概览
简要总结
The researchers are investigating a new treatment for white matter injury, which is a common type of brain injury in premature babies. The drug, clemastine, is experimental. This means that the drug is not approved by the Food and Drug Administration (FDA) for the treatment of white matter injury. The main purpose of this study is to learn whether clemastine is safe to give to infants with white matter injury. The researchers also want to understand how much clemastine gets into an infant's body when the medication is taken by mouth, and how long it stays in the body.
详细描述
Preterm white matter injury (WMI) is the most common type of brain injury in premature infants and is associated with adverse neurological outcomes, including motor and cognitive disability and seizures. Preterm WMI involves an arrest of differentiation in the oligodendroglial cell lineage and a failure of normal developmental myelination. No therapies exist that directly promote brain repair and myelination or can be given at the time that preterm WMI has been identified and is likely most amenable to treatment. The lack of available treatments inherently limits the possibility for functional recovery in affected infants. Clemastine is an antihistamine and antimuscarinic agent that was identified in a high-throughput screen of FDA-approved compounds that significantly promote myelination in vitro. Clemastine was subsequently shown to promote myelination and improve functional recovery in multiple animal models of WMI, including preterm WMI, and induces remyelination in adult patients with multiple sclerosis. Clemastine is therefore an ideal potential candidate treatment for preterm WMI. The investigators will be conducting a Phase I/Ib open label dose-escalation and dose expansion study to test the safety and pharmacokinetics of oral clemastine treatment in neonates with preterm WMI.
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
- 3 Weeks 至 20 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Born at ≤32 weeks gestational age based on prenatal ultrasound or last menstrual period (LMP).
- •Current age of between 35-41 weeks PMA.
- •Imaging evidence of white matter injury on any scan as defined by either brain MRI or cUS criteria:
- •Brain MRI with Grade Ib WMI or higher based on the Martinez-Biarge et al 2016 criteria.
- •cUS with Grade 3 or higher white matter abnormalities based on Miller et al 2003 criteria.
- •Currently hospitalized in a participating intensive care nursery.
排除标准
- •Known or suspected metabolic or chromosomal disorder or major congenital anomalies
- •Major intracranial hemorrhage within the last 1 week or intracranial hemorrhage of any age that is not controlled or continuing to cause significant mass effect or midline shift.
- •History of cardiac arrhythmia or current ongoing tachycardia with baseline heart rate >10% age expected norms.
- •Hypotension requiring ongoing vasopressor or inotropic support.
- •Not able to receive enteral medications.
- •Clinically significant sedation due to critical illness or medications.
- •Concomitant use of any other putative neuroprotective or myelination promoting therapy as determined by the investigator.
- •Serum creatinine, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) >2x the upper limit of normal for age.
- •Family history of epilepsy due to a confirmed or suspected genetic cause.
- •History of confirmed seizure activity.
- •If ≥36 weeks postmenstrual age, required respiratory support greater than 2L/min, noninvasive positive airway pressure, or mechanical ventilation upon reaching 36 weeks postmenstrual age due to diagnosis of moderate or severe BPD.
- •If less than 36 weeks postmenstrual age, currently requiring respiratory support greater than 2L/min, noninvasive positive airway pressure, or mechanical ventilation, unless respiratory support is being given to promote lung development and not due to clinical need.
- •Major medical conditions, laboratory abnormalities, or concurrent treatments that, in opinion of the investigator, may affect interpretation of study results or patient safety.
研究组 & 干预措施
Dose level 4
干预措施: Clemastine fumarate (Drug)
Dose level 1
Dose level 1 (0.01 mg/kg/day)
干预措施: Clemastine fumarate (Drug)
Dose level 2
Dose level 2 (0.03 mg/kg/day)
干预措施: Clemastine fumarate (Drug)
Dose level 3
Dose level 3 (0.05 mg/kg/day)
干预措施: Clemastine fumarate (Drug)
结局指标
主要结局
Number of subjects who experience dose limiting toxicity
时间窗: From study drug administration through 30 days after the last dose
The primary objective is to assess the safety of oral clemastine in preterm neonates with white matter injury (WMI) who have reached at least 35 weeks postmenstrual age (PMA), as measured by the number of subjects who experience dose limiting toxicity (DLT). PMA equals the gestational age (GA) at birth plus chronological age.
次要结局
- Number of patients who experience any adverse events related to the study drug(From study drug administration through 30 days after the last dose)
- Pharmacokinetics of Clemastine in Preterm Neonates(From day 1 through day 15)
研究者
Bridget LaMonica Ostrem, M.D., Ph.D.
Assistant Clinical Professor of Neurology
University of California, San Francisco