Clinical trial NCT03655223: Early Check: Expanded Screening in Newborns
Official title: Early Check: A Collaborative Innovation to Facilitate Pre-Symptomatic Clinical Trials in Newborns
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Spinal Muscular Atrophy
Fragile X Syndrome
Fragile X - Premutation
Duchenne Muscular Dystrophy
Hyperinsulinemic Hypoglycemia, Familial 1
Diabetes Mellitus
Adrenoleukodystrophy, Neonatal
Medium-chain Acyl-CoA Dehydrogenase Deficiency
Very Long Chain Acyl Coa Dehydrogenase Deficiency
Beta-ketothiolase Deficiency
Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency
Primary Hyperoxaluria Type 1
Congenital Bile Acid Synthesis Defect Type 2
Pyridoxine-Dependent Epilepsy
Hereditary Fructose Intolerance
Hypophosphatasia
Hyperargininemia
Mucopolysaccharidosis Type 6
Argininosuccinic Aciduria
Citrullinemia, Type I
Wilson Disease
Maple Syrup Urine Disease, Type 1A
Maple Syrup Urine Disease, Type 1B
Biotinidase Deficiency
Neonatal Severe Primary Hyperparathyroidism
Intrinsic Factor Deficiency
Usher Syndrome Type 1D/F Digenic (Diagnosis)
Cystic Fibrosis
Stickler Syndrome Type 2
Stickler Syndrome Type 1
Alport Syndrome, Autosomal Recessive
Alport Syndrome, X-Linked
Carbamoyl Phosphate Synthetase I Deficiency Disease
Carnitine Palmitoyl Transferase 1A Deficiency
Carnitine Palmitoyltransferase II Deficiency
Cystinosis
Chronic Granulomatous Disease
Cerebrotendinous Xanthomatoses
Maple Syrup Urine Disease, Type 2
Severe Combined Immunodeficiency Due to DCLRE1C Deficiency
Thyroid Dyshormonogenesis 6
Thyroid Dyshormonogenesis 5
Supravalvar Aortic Stenosis
Factor X Deficiency
Hemophilia A
Hemophilia B
Tyrosinemia, Type I
Fructose 1,6 Bisphosphatase Deficiency
Glycogen Storage Disease Type I
G6PD Deficiency
Glycogen Storage Disease II
Galactokinase Deficiency
Mucopolysaccharidosis Type IV A
Galactosemias
Guanidinoacetate Methyltransferase Deficiency
Agat Deficiency
Glutaryl-CoA Dehydrogenase Deficiency
Gtp Cyclohydrolase I Deficiency
Hyperinsulinism-Hyperammonemia Syndrome
Primary Hyperoxaluria Type 2
3-Hydroxyacyl-CoA Dehydrogenase Deficiency
Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency
Mitochondrial Trifunctional Protein Deficiency
Sickle Cell Disease
Beta-Thalassemia
Holocarboxylase Synthetase Deficiency
3-Hydroxy-3-Methylglutaric Aciduria
Primary Hyperoxaluria Type 3
Hermansky-Pudlak Syndrome 1
Hermansky-Pudlak Syndrome 4
Apparent Mineralocorticoid Excess
HSDB
CBAS1
Mucopolysaccharidosis Type 2
Mucopolysaccharidosis Type 1
Severe Combined Immunodeficiency, X Linked
Severe Combined Immunodeficiency Due to IL-7Ralpha Deficiency
Diabetes Mellitus, Permanent Neonatal
Isovaleric Acidemia
Severe Combined Immunodeficiency T-Cell Negative B-Cell Positive Due to Janus Kinase-3 Deficiency (Disorder)
Jervell and Lange-Nielsen Syndrome 2
Hyperinsulinemic Hypoglycemia, Familial, 2
Diabetes Mellitus, Permanent Neonatal, With Neurologic Features
Jervell and Lange-Nielsen Syndrome 1
Lysosomal Acid Lipase Deficiency
CblF
3-Methylcrotonyl CoA Carboxylase 1 Deficiency
3-Methylcrotonyl CoA Carboxylase 2 Deficiency
Waardenburg Syndrome Type 2A
Methylmalonic Aciduria cblA Type
Methylmalonic Aciduria cblB Type
Methylmalonic Aciduria and Homocystinuria Type cblC
MAHCD
Methylmalonic Aciduria Due to Methylmalonyl-CoA Mutase Deficiency
Congenital Disorder of Glycosylation Type 1B
Mthfr Deficiency
Methylcobalamin Deficiency Type Cbl G (Disorder)
Methylcobalamin Deficiency Type cblE
Usher Syndrome, Type 1B
N-acetylglutamate Synthase Deficiency
Ornithine Transcarbamylase Deficiency
Phenylketonurias
Waardenburg Syndrome Type 1
Congenital Hypothyroidism
Propionic Acidemia
Usher Syndrome, Type 1F
Pancreatic Agenesis 1
Hereditary Hypophosphatemic Rickets
Glycogen Storage Disease IXB
Glycogen Storage Disease IXC
MOWS
Epilepsy, Early-Onset, Vitamin B6-Dependent
Pyridoxal Phosphate-Responsive Seizures
Pituitary Hormone Deficiency, Combined, 1
Ptsd
Dihydropteridine Reductase Deficiency
Severe Combined Immunodeficiency Due to RAG1 Deficiency
Severe Combined Immunodeficiency Due to RAG2 Deficiency
Retinoblastoma
Multiple Endocrine Neoplasia Type 2B
Pseudohypoaldosteronism, Type I
Liddle Syndrome
Biotin-Responsive Basal Ganglia Disease
SCD
DIAR1
GSD1C
Acrodermatitis Enteropathica
Thyroid Dyshormonogenesis 1
Riboflavin Transporter Deficiency
Waardenburg Syndrome, Type 2E
SRD
Congenital Lipoid Adrenal Hyperplasia Due to STAR Deficiency
Barth Syndrome
Adrenocorticotropic Hormone Deficiency
Transcobalamin II Deficiency
Thyroid Dyshormonogenesis 3
Segawa Syndrome, Autosomal Recessive
Autosomal Recessive Nonsyndromic Hearing Loss
Thyroid Dyshormonogenesis 2A
Congenital Isolated Thyroid Stimulating Hormone Deficiency
Hypothyroidism Due to TSH Receptor Mutations
Usher Syndrome Type 1C
Usher Syndrome Type 1G (Diagnosis)
Von Willebrand Disease, Type 3
Combined Immunodeficiency Due to ZAP70 Deficiency
Adenine Phosphoribosyltransferase Deficiency
Metachromatic Leukodystrophy
Canavan Disease
Menkes Disease
Carbonic Anhydrase VA Deficiency
Developmental and Epileptic Encephalopathy 2
17 Alpha-Hydroxylase Deficiency
Smith-Lemli-Opitz Syndrome
Krabbe Disease
Glutathione Synthetase Deficiency
Mucopolysaccharidosis Type 7
Rett Syndrome
Molybdenum Cofactor Deficiency, Type A
Niemann-Pick Disease, Type C1
Niemann-Pick Disease Type C2
Ornithine Aminotransferase Deficiency
3-Phosphoglycerate Dehydrogenase Deficiency
Leber Congenital Amaurosis 2
Dravet Syndrome
Mucopolysaccharidosis Type 3 A
Ornithine Translocase Deficiency
Carnitine-acylcarnitine Translocase Deficiency
Glucose Transporter Type 1 Deficiency Syndrome
Creatine Transporter Deficiency
Niemann-Pick Disease Type A
Pitt Hopkins Syndrome
Tuberous Sclerosis 1
Tuberous Sclerosis 2
Ataxia With Isolated Vitamin E Deficiency
Angelman Syndrome
Prader-Willi Syndrome
Homocystinuria
Permanent Neonatal Diabetes Mellitus
Transient Neonatal Diabetes Mellitus
Factor VII Deficiency
Glycogen Storage Disease Type IXA1
Glycogen Storage Disease, Type IXA2
Glycogen Storage Disease IC
Glycogen Storage Disease Type IB
Central Hypoventilation Syndrome With or Without Hirschsprung Disease
Keywords: Newborn Screening
Rare Disorders
Genetic Counseling
Families
Development
Risk
Genetic Sequencing
Lead sponsor: RTI International
Sponsor class: OTHER
Collaborators: name: University of North Carolina, Chapel Hill
name: The John Merck Fund
name: Duke University
name: Wake Forest University
name: North Carolina Department of Health and Human Services
name: National Center for Advancing Translational Sciences (NCATS)
name: Cure SMA
name: The National Fragile X Foundation
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Asuragen, Inc.
name: Sarepta Therapeutics, Inc.
name: Muscular Dystrophy Association
name: The Leona M. and Harry B. Helmsley Charitable Trust
name: Juvenile Diabetes Research Foundation
name: Janssen Pharmaceuticals
name: GeneDx
name: Illumina, Inc.
First posted: 2018-08-31
Enrollment: 30000
Sex: ALL
Minimum age (years): 1
Maximum age (years): 31
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Newborns born in North or South Carolina who are less than 31 days old

Brief summary: Early Check provides voluntary screening of newborns for a selected panel of conditions. The study has three main objectives: 1) develop and implement an approach to identify affected infants, 2) address the impact on infants and families who screen positive, and 3) evaluate the Early Check program. The Early Check screening will lead to earlier identification of newborns with rare health conditions in addition to providing important data on the implementation of this model program. Early diagnosis may result in health and development benefits for the newborns. Infants who have newborn screening in North Carolina will be eligible to participate, equating to over 120,000 eligible infants a year. Over 95% of participants are expected to screen negative. Newborns who screen positive and their parents are invited to additional research activities and services. Parents can enroll eligible newborns on the Early Check electronic Research Portal. Screening tests are conducted on residual blood from existing newborn screening dried blood spots. Confirmatory testing is provided free-of-charge for infants who screen positive, and carrier testing is provided to mothers of infants with fragile X. Affected newborns have a physical and developmental evaluation. Their parents have genetic counseling and are invited to participate in surveys and interviews. Ongoing evaluation of the program includes additional parent interviews.

Detailed description: "Background" Newborn screening (NBS) is a state-based public health program that screens babies for a panel of over 30 conditions. It is estimated that about 12,500 newborns each year in the United States are identified with one of the conditions screened in NBS, with each child receiving the benefit of early treatment. For inclusion in newborn screening there must be evidence that pre-symptomatic treatment is more effective than treatment after clinical presentation. Most conditions proposed for newborn screening are rare, however, and researchers have difficulty identifying sufficient numbers of babies to test the benefits of pre-symptomatic identification and treatment. This lack of data is central to challenges that the U.S. Department of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) faces when making federal recommendations to states on which conditions should be included in newborn screening programs. ACHDNC is often asked to consider conditions for inclusion in newborn screening for which there is limited evidence of the natural history, prevalence, and especially about the benefit of early treatment.

"Rationale" That evidence gap, especially in the rare disease context, makes it important to develop and test a system to efficiently generate high-quality data about conditions that have the potential to be candidates for state newborn screening. The Early Check program will address this gap through screening newborns for a carefully selected panel of conditions, offered under a research protocol with biological maternal permission, except in cases where there is a transfer or loss of custody. In cases with a transfer/loss of custody, a legal guardian can grant permission for the infant to join Early Check. Early Check will identify pre-symptomatic infants with rare disorders, accelerate the acquisition of data on the early natural history of rare disorders, and demonstrate the feasibility of a statewide program to offer voluntary opt-in newborn screening for a panel of conditions not currently included in states' standard newborn screening. Further, Early Check will facilitate the public health 'on-boarding' of conditions that are ultimately recommended for state newborn screening programs.

The initial panel of conditions screened in the Early Check program will change over the course of the study. Previously screened conditions have included spinal muscular dystrophy (SMA), fragile X syndrome (FXS), and Duchenne muscular dystrophy (DMD) and related neuromuscular conditions that result in increased levels of creatine kinase (CK-MM). SMA has an approved treatment, nusinersen, which has been demonstrated to improve outcomes in infants with infantile-onset SMA. In addition, infants with a shorter disease duration compared to a longer disease duration had improved outcomes after the start of treatment with nusinersen, suggesting that earlier identification of SMA would benefit affected infants. There is also an approved gene therapy, Zolgensma, for SMA. FXS does not have an approved treatment, although there is evidence that early behavioral intervention services may improve outcomes. Given that the diagnosis of FXS is made on average after the child is three years old, early identification through the screening of newborns may provide benefit to the child. These conditions are rare; SMA has an estimated incidence of 1 in \~10,000, DMD has an estimated incidence of 1 in 4000-5000 males, and FXS has an estimated incidence of 1 in \~4,000 males and 1 in \~4,000-6,000 females. We also completed a sub-study with a secondary permission process that offers mothers the choice to obtain additional data about the gene that causes FXS: specifically, whether the infant has a premutation in the gene, which has an uncertain impact on the infant's learning and development. This uncertainty is the reason why premutation results are offered separately under a sub-study. DMD causes progressive inflammation, fibrosis, and muscle fiber degradation, and weakness. DMD has traditionally been treated with physical therapy, corticosteroids, and ACE inhibitors to delay the progression of skeletal muscle and cardiac damage. In 2016, the FDA approved Eteplirsen (Exondys, 51) a promising treatment for a subset of patients with DMD. In 2017 the FDA approved Emflaza, a corticosteroid also known as deflazacort. In 2019 the FDA approved Vyondys 53 and in 2020 the FDA approved Viltepso for mutations amenable to exon 53 skipping. Early diagnosis allows for treatments that might work best if used presymptomatically.

The current screening panel includes 182 genes for rare conditions that are highly actionable by age 2. An optional secondary panel includes 32 genes that are less actionable, or for which there are treatments under trial, with an additional optional third panel that screens for genetic risk for Type 1 Diabetes.

For a wide range of rare disorders there is evidence that a delayed diagnosis (i.e., the frequently-described diagnostic odyssey as parents search for a diagnosis) can have negative health outcomes on children who miss out on treatments or interventions and on families who experience negative psychosocial impact

In the future, Early Check will continue to integrate new conditions to the screening platform as science advances and funding is secured, and conditions may be removed from the screening platform as associated research questions are answered and/or conditions achieve inclusion in state newborn screening programs (as was the case with SMA and FXS).

The overall research question is whether Early Check is an effective onboarding program to inform newborn screening policy decision-making.

Early Check will also provide the infrastructure to facilitate translational research studies and clinical trials. A dilemma in research in rare diseases is a lack of sufficient numbers of presymptomatic patients. New treatments are being developed for rare diseases at a rapid pace. Presymptomatic treatment often has the best potential for effective treatment. Currently, early identification and intervention is based on the prenatal or early diagnosis of a sibling of a patient with known disease, which greatly limits the numbers of presymptomatic patients available for trials. Newborn screening has the greatest potential to identify presymptomatic infants. Ultimately the research program should more rapidly advance understanding of diseases and treatments, reducing the length of time for appropriate conditions to be added to the recommended panel for inclusion in state newborn screening programs, and provide early identification of affected newborns.

Overall, this project will provide important information about the success of Early Check to feasibly and acceptably implement a large scale, electronically-mediated research approach to accurately identify affected infants. Results of the research activities and the ongoing quality assessment will be used to inform the most efficient and judicious translation of expanded newborn screening into public health in ways that maximize benefit and minimize potential risk of harm to children and families.

Eligibility criteria: Inclusion Criteria:

* Newborn has newborn screening in North Carolina
* Newborn lives in North Carolina or South Carolina
* Newborn is less than 31 days old
* Person giving consent must have legal custody of the newborn. When the mother retains custody, they must be the person to give consent.
* Person giving consent must be able to interact with the online permission portal (available in English and Spanish) and give permission online

Exclusion Criteria:

* A newborn screening (NBS) sample is unavailable for the newborn
* Insufficient NBS sample remains to conduct the screening

Primary outcomes:
measure: Incidence Rates: Number of newborns who screen positive comparative to the whole sample
timeFrame: Every 6 months for approximately three years
Secondary outcomes:
measure: Impact of Screening: Semi-structured parent interviews.
timeFrame: Measured within 6 months of participant screening results
Other outcomes:
Locations:
city: Research Triangle Park
country: United States
facility: RTI International
state: North Carolina
Study officials:
affiliation: RTI International
name: Don Bailey, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Finkel, Mercuri, Darras, Kuntz, Kirschner et al, 2017
citation: Birnkrant, et al, 2018
citation: Winarni, Schneider, Borodyanskara, & Hagerman, 2012
citation: Bailey, Raspa, Bishop & Holiday, 2009
citation: Gehtland LM, Paquin RS, Andrews SM, Lee AM, Gwaltney A, Duparc M, Pfaff ER, Bailey DB Jr. Using a Patient Portal to Increase Enrollment in a Newborn Screening Research Study: Observational Study. JMIR Pediatr Parent. 2022 Feb 10;5(1):e30941. doi: 10.2196/30941.
citation: Bailey DB Jr, Gehtland LM, Lewis MA, Peay H, Raspa M, Shone SM, Taylor JL, Wheeler AC, Cotten M, King NMP, Powell CM, Biesecker B, Bishop CE, Boyea BL, Duparc M, Harper BA, Kemper AR, Lee SN, Moultrie R, Okoniewski KC, Paquin RS, Pettit D, Porter KA, Zimmerman SJ. Early Check: translational science at the intersection of public health and newborn screening. BMC Pediatr. 2019 Jul 17;19(1):238. doi: 10.1186/s12887-019-1606-4.