An Adaptive Clinical Trial of BeginNGS Newborn Screening for Hundreds of Genetic Diseases by Genome Sequencing
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 10,000
- 试验地点
- 2
- 主要终点
- Comparison of the clinical utility of BeginNGS and standard of care (state NBS), defined by the proportion of enrollees likely to benefit (likely to have an improved outcome) from an indicated therapeutic intervention
研究概览
简要总结
The goal of this clinical trial is to test a new method for newborn screening using whole genome sequencing, called BeginNGS. Parents will be approached to provide informed consent to enroll their newborns in prenatal, postnatal, and outpatient settings. The main questions this study aims to answer are:
What is the utility of BeginNGS as compared to state newborn screening? What is the acceptability and feasibility of BeginNGS as compared to state newborn screening? What is the cost effectiveness of BeginNGS as compared to state newborn screening?
Enrolled newborns will have a blood sample taken and will receive the BeginNGS test. Newborns will have also had the state newborn screening test.
详细描述
Each year 98% of US newborns receive screening (NBS) of dried blood spots (DBS) for at least 35 Recommended Uniform Screening Panel (RUSP) genetic disorders for diagnosis and treatment at/before onset of symptoms. About 6,600 true positive infants are identified per year. NBS is well-accepted and has proven clinical utility. Between 2010 and 2022, however, while many new therapeutic interventions for childhood genetic diseases showed clinical utility and/or were approved by the Food and Drug Administration (FDA), only 6 disorders were added to the RUSP. As a result, ~700 childhood genetic diseases have effective treatments but are not yet screened by NBS, and affected children experience delayed diagnosis and treatment, and poor outcomes. To solve this problem the investigators are developing BeginNGS - NBS by genome sequencing (GS) of DBS for, ultimately, ~700 severe, childhood genetic diseases with effective therapeutic interventions. BeginNGS is adaptive: genetic disorders are added (or removed) as evidence emerges that early treatment improves (or does not improve) outcomes. BeginNGS version 1 (v1, 388 genetic disorders) had good sensitivity (88.8%) and false positive rate (0.27%) in a retrospective study of 458,000 subjects. An exploratory prospective clinical trial comparing BeginNGS v2 (with 409 disorders) and rapid diagnostic genome sequencing (RDGS) identified reportable findings in 24 (34%) of 71 acutely ill newborns who were not suspected of having a genetic disease. Only 2 of those disorders were detected by standard NBS. The investigators propose a single group, multicenter, adaptive clinical trial to compare utility, acceptability, feasibility, and cost effectiveness of BeginNGS (experimental intervention) with standard NBS (control) in a minimum of 10,000 neonates (aged <28 days, maximum of 100,000). The primary objective of the trial is to generate evidence to support broad implementation of BeginNGS. An adaptive design was chosen rather than a traditional, fixed design to allow accumulating results to make the trial more efficient, informative, and ethical by addition or removal of BeginNGS disorders and genetic variants, population enrichment (for minority racial, ethnic, and ancestral groups), and sample size re-estimation. Adaptive design will also facilitate meta-analysis with other clinical trials of NBS-by-GS, providing greater power to test utility in ultra-rare genetic diseases. NBS-by-GS has the potential to transform the way childhood genetic diseases are diagnosed and treatments started. Preliminary data suggest that national adoption of BeginNGS in all births has the potential to improve outcomes of >50,000 US children per year.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Screening
- 盲法
- None
入排标准
- 年龄范围
- 1 Day 至 28 Days（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Neonates (<28 days old) at enrollment sites.
- •Parents must have identified a primary care provider (or group).
排除标准
- •Neonates whose mother is less than 18 years of age.
- •Neonates who are wards of the state.
- •Neonates whose parent/legal guardian is unable to provide consent.
- •Parents with a home address outside the US or jurisdiction of the enrollment sites.
- •Neonates or fetuses who are ill and in whom enrollment or sampling is anticipated to interfere with healthcare provision at delivery. For example, fetuses or neonates who are likely to require transfer to a higher level of care, such as to a Level IV NICU upon delivery.
- •Neonates who are under consideration for a rapid diagnostic genome sequence or other diagnostic genetic testing.
- •Neonates who are not expected to survive the neonatal period.
研究组 & 干预措施
Enrollees
Enrolled infants will receive the BeginNGS test in addition to the state newborn screen.
干预措施: BeginNGS Test (Genetic)
结局指标
主要结局
Comparison of the clinical utility of BeginNGS and standard of care (state NBS), defined by the proportion of enrollees likely to benefit (likely to have an improved outcome) from an indicated therapeutic intervention
时间窗: 5 years
The proportion of enrollees likely to benefit (likely to have an improved outcome) from an indicated therapeutic intervention (as per an electronic clinical management system, Genome-to-Treatment, GTRx)
次要结局
- Utility secondary outcome 11(5 years)
- Utility secondary outcome 2(5 years)
- Acceptability outcome 2(5 years)
- Utility secondary outcome 3(5 years)
- Utility secondary outcome 8(5 years)
- Feasibility (ability of the study to be undertaken as designed) outcome 1(5 years)
- Feasibility (ability of the study to be undertaken as designed) outcome 5(5 years)
- Accuracy outcome 1(5 years)
- Utility secondary outcome 4(5 years)
- Utility secondary outcome 5(5 years)
- Utility secondary outcome 7(5 years)
- Utility secondary outcome 10(5 years)
- Acceptability outcome 4(5 years)
- Feasibility (ability of the study to be undertaken as designed) outcome 3(5 years)
- Accuracy outcome 2(5 years)
- Utility secondary outcome 1(5 years)
- Utility secondary outcome 9(5 years)
- Acceptability outcome 3(5 years)
- Utility secondary outcome 6(5 years)
- Acceptability outcome 1(5 years)
- Feasibility (ability of the study to be undertaken as designed) outcome 2(5 years)
- Cost effectiveness outcome 2(5 years)
- Cost effectiveness outcome 3(5 years)
- Feasibility outcome 6(5 years)
- Feasibility (ability of the study to be undertaken as designed) outcome 4(5 years)
- Cost effectiveness outcome 1(5 years)
- Cost effectiveness outcome 4(5 years)
- Feasibility outcome 7(5 years)
- Utility secondary outcome 12(5 years)
研究者
Stephen F. Kingsmore
President and CEO
Rady Pediatric Genomics & Systems Medicine Institute