PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- The number of participants with improvement or resolution of hydrops (if present).
研究概览
简要总结
For detailed information, please view our study website: https://pearltrial.ucsf.edu/
The investigators aims to determine the the maternal and fetal safety and feasibility of in utero fetal enzyme replacement therapy in fetuses with Lysosomal Storage Diseases.
详细描述
Because fetuses with these LSDs are at increased risk of serious perinatal morbidity and mortality, particularly in the setting of Non-Immune Hydrops Fetalis (NIHF), the administration of the approved enzyme therapy in utero has the potential to significantly improve outcomes for affected fetuses. The perinatal death rate associated with NIHF ranges from 30 to 75%, so development of an in utero approach to treatment could be of significant benefit. The in utero period has been shown to be a time of relative fetal tolerance to immune stimuli, and this tolerance may lead to improved response to ERT in situations where postnatal initiation instead leads to antibody development and impaired response to treatment. It is also probable that in some cases, initiation of ERT in utero leads to improved neurodevelopmental outcomes if the replaced enzyme impacts the neurologic system during critical periods of development.
This is a phase 1 clinical trial to determine the safety and feasibility of fetal enzyme replacement therapy in fetuses with LSD
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Live male or female fetuses at 18 0/7 weeks to 34 6/7 weeks gestation
- •Diagnosis of one of the 8 included LSDs in utero by genetic or enzymatic analyses performed on amniotic fluid, fetal blood, placental tissue, or other samples through chorionic villus sampling (CVS), amniocentesis, cordocentesis, cell free fetal DNA, or other procedures. In the event that parents are identified as genetic carriers for a LSD, diagnostic testing for the fetus would be performed to confirm the diagnosis
- •Pregnant women age 18 years to 50 years, carrying a live male or female fetus at 18 0/7 weeks to 34 6/7 weeks gestation
- •Identified through the above listed means to be carrying a fetus with an LSD.
- •Ability to give written informed consent and comply with the requirements of the study.
排除标准
- •Fetuses with a concurrent severe structural anomaly
- •Fetuses with an additional pathogenic genetic variant not related to the underlying LSD that contribute a significant risk of morbidity or mortality.
- •Hydrops fetalis will not be an exclusion criterion because ERT has the possibility of significant benefit in this situation.
- •Women with one or more significant comorbidities that would preclude fetal intervention including, but not limited to:
- •inability to complete the procedure secondary to maternal body habitus or placental location
- •significant cardiopulmonary disease
- •mirror syndrome
- •end organ failure
- •altered mental status
- •placental abruption
- •active preterm labor
- •preterm premature rupture of membranes.
- •Mother will require therapeutic dosing of anticoagulation within 24 hours prior to or following the intervention.
研究组 & 干预措施
Experimental: in utero enzyme replacement therapy
ERT will be delivered in utero. Typically, the target of the procedure to administer in utero ERT will be the umbilical vein near the insertion of the umbilical cord into the placenta. The dose of the ERT will be dependent on the specific disease process and enzyme being replaced, and the estimated weight of the fetus. The dosage will be the same as the recommended weight-based postnatal dosing, adjusted for estimated fetal weight. IUERT will be repeated every 2-4 weeks, which is an interval consistent with the standard of care for IUTs (every 2-4 weeks) to avoid excessive access through the umbilical vein. This interval is also consistent with the half-life of each relevant enzyme.
干预措施: Aldurazyme (laronidase) (Drug)
结局指标
主要结局
The number of participants with improvement or resolution of hydrops (if present).
时间窗: 6 years
Improvement of hydrops via ultrasound and echocardiogram results (if present).
Number of participants to receive the full initial, weight-based dose of enzyme replacement therapy through the fetal umbilical vein, and subsequent doses throughout the pregnancy.
时间窗: 6 years
full dose administration compared to the need to halt the intervention prior to administration of a full dose.
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
时间窗: 6 years
Adverse and serious adverse events including, but not limited to, death within 24 hours after the procedure, stillbirth, death prior to initial hospital discharge,increased response with antibody development above that expected with postnatal ERT, and serious related or serious unexpected adverse events exceeding those expected with the natural history of treated disease during the first five years of life, assessed by CTCAE v5.0.
Number of participants with the presence and levels of glycosaminoglycans (GAGs) in urine.
时间窗: 6 years
Laboratory analysis of urine for GAG levels.
次要结局
- Number of participants that show measured levels of antibodies against the enzyme.(6 years)
研究者
Tippi Mackenzie
Professor of Surgery
University of California, San Francisco