Early Check: Expanded Screening in Newborns

Diabetes Mellitus Clinical Trial

Official title: Early Check: A Collaborative Innovation to Facilitate Pre-Symptomatic Clinical Trials in Newborns

Status Enrolling by invitation

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Acrodermatitis Enteropathica
• Adenine Phosphoribosyltransferase Deficiency
• Adrenal Hyperplasia, Congenital
• Adrenogenital Syndrome
• Adrenoleukodystrophy
• Amino Acid Metabolism, Inborn Errors
• Anemia, Sickle Cell
• Angelman Syndrome
• Aortic Valve Stenosis
• Aphasia, Primary Progressive
• Apparent Mineralocorticoid Excess
• Argininosuccinic Aciduria
• Arthritis
• Barth Syndrome
• Basal Ganglia Diseases
• Beta-Thalassemia
• Biotinidase Deficiency
• Blindness
• Brain Diseases
• Canavan Disease
• Carbamoyl-Phosphate Synthase I Deficiency Disease
• Carnitine Palmitoyltransferase II Deficiency
• Chronic Granulomatous Disease
• Citrullinemia
• Congenital Disorders of Glycosylation
• Congenital Hyperinsulinism
• Congenital Hypothyroidism
• Connective Tissue Diseases
• Craniofacial Abnormalities
• Cystic Fibrosis
• Cystinosis
• Deficiency Diseases
• Diabetes Mellitus
• Disease
• Dravet Syndrome
• Duchenne Muscular Dystrophy
• Endocrine Gland Neoplasms
• Endocrine System Diseases
• Epilepsies, Myoclonic
• Epilepsy
• Eye Diseases, Hereditary
• Factor VII Deficiency
• Factor X Deficiency
• Familial Hypophosphatemic Rickets
• Fragile X - Premutation
• Fragile X Syndrome
• Frontotemporal Dementia
• Fructose Intolerance
• G6PD Deficiency
• Galactosemias
• Glucose Transporter Type 1 Deficiency Syndrome
• Glucosephosphate Dehydrogenase Deficiency
• Glycogen Storage Disease
• Glycogen Storage Disease II
• Glycogen Storage Disease Type I
• Glycogen Storage Disease Type IB
• Glycogen Storage Disease Type II
• Granulomatous Disease, Chronic
• Gyrate Atrophy
• Hearing Loss
• Hearing Loss, Sensorineural
• Hemophilia A
• Hemophilia B
• Hereditary Fructose Intolerance
• Hermanski-Pudlak Syndrome
• Hirschsprung Disease
• Homocystinuria
• Hyperaldosteronism
• Hyperammonemia
• Hyperargininemia
• Hyperinsulinism
• Hyperinsulinism-Hyperammonemia Syndrome
• Hyperoxaluria, Primary
• Hyperparathyroidism
• Hyperparathyroidism, Primary
• Hyperplasia
• Hypoglycemia
• Hypophosphatasia
• Hypothyroidism
• Hypoventilation
• Immunologic Deficiency Syndromes
• Infant, Newborn, Diseases
• Krabbe Disease
• Leber Congenital Amaurosis
• Leber Congenital Amaurosis 2
• Leukodystrophy, Globoid Cell
• Leukodystrophy, Metachromatic
• Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency
• Lysosomal Acid Lipase Deficiency
• Maple Syrup Urine Disease
• Medium-chain Acyl-CoA Dehydrogenase Deficiency
• Menkes Disease
• Metabolic Diseases
• Metabolism, Inborn Errors
• Metachromatic Leukodystrophy
• Mitochondrial Trifunctional Protein Deficiency
• Molybdenum Cofactor Deficiency, Type A
• Mucopolysaccharidoses
• Mucopolysaccharidosis I
• Mucopolysaccharidosis II
• Mucopolysaccharidosis III
• Mucopolysaccharidosis IV
• Mucopolysaccharidosis Type 7
• Mucopolysaccharidosis VI
• Multiple Endocrine Neoplasia
• Multiple Endocrine Neoplasia Type 2a
• Multiple Endocrine Neoplasia Type 2b
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne
• N-acetylglutamate Synthase Deficiency
• Nephritis, Hereditary
• Nesidioblastosis
• Niemann-Pick Disease, Type C
• Niemann-Pick Disease, Type C1
• Niemann-Pick Diseases
• Ornithine Transcarbamylase Deficiency
• Permanent Neonatal Diabetes Mellitus
• Peroxisomal Disorders
• Phenylketonurias
• Pick Disease of the Brain
• Pitt Hopkins Syndrome
• Prader-Willi Syndrome
• Primary Hyperoxaluria Type 1
• Primary Hyperoxaluria Type 2
• Primary Hyperoxaluria Type 3
• Propionic Acidemia
• Protein Deficiency
• Pseudohypoaldosteronism
• Ptsd
• Retinal Detachment
• Retinoblastoma
• Rett Syndrome
• Rickets
• SCD
• Sclerosis
• Seizures
• Severe Combined Immunodeficiency
• Severe Combined Immunodeficiency Due to RAG1 Deficiency
• Severe Combined Immunodeficiency, X Linked
• Sickle Cell Disease
• Smith-Lemli-Opitz Syndrome
• Spinal Muscular Atrophy
• Stickler Syndrome Type 1
• Stickler Syndrome Type 2
• Syndrome
• Thalassemia
• Thyroid Diseases
• Tuberous Sclerosis
• Tyrosinemia, Type I
• Tyrosinemias
• Usher Syndrome, Type 1B
• Usher Syndromes
• Very Long Chain Acyl Coa Dehydrogenase Deficiency
• Vitamin E Deficiency
• Von Willebrand Diseases
• Waardenburg Syndrome
• Wilson Disease
• Wolman Disease
• X-Linked Combined Immunodeficiency Diseases
• Xanthomatosis, Cerebrotendinous

• NCT number: NCT03655223
• Study type: Observational
• Source: RTI International
• Status: Enrolling by invitation
• Start date: October 15, 2018
• Completion date: December 31, 2025