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Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients (TED)

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ClinicalTrials.gov Identifier: NCT03455881
Recruitment Status : Recruiting
First Posted : March 7, 2018
Last Update Posted : March 21, 2019
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Columbia University
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Brief Summary:
The investigators propose a preliminary study performing exome sequencing on samples from patients and their biologically related family members with tracheal and esophageal birth defects (TED). The investigators will use advanced, non-invasive magnetic resonance imaging (MRI) techniques to assess tracheal esophageal, lung, and cardiac morphology and function in Neonatal Intensive Care Unit (NICU) patients. The purpose of this study is to determine if patients diagnosed with TED and similar disorders carry distinct mutations that lead to predisposition and to determine if an MRI is a more effective way of evaluating the TEDs.

Condition or disease
Tracheoesophageal Fistula Esophageal Atresia Laryngeal Cleft Tracheal Stenosis Bronchial Stenosis Esophageal Bronchus Congenital High Airway Obstruction Syndrome

Detailed Description:
TEDs (tracheal esophageal birth defects) are a life threatening congenital disorder with multiple long term complications. Occurring in 1 in 2,500 to 4,500 live births, TEDs include tracheal malformations such as tracheomalacia, laryngotracheoesophageal clefts, tracheal agenesis, tracheal stenosis, tracheal bronchus, esophageal bronchus and esophageal malformations such as esophageal atresia (EA), tracheal esophageal fistula (TEF), and esophageal duplication. TEDs likely have a genetic basis, but in most cases the specific mutations are unknown. The most commonly diagnosed TED, requiring neonatal hospitalization, is EA/TEF. The familial recurrence rate of EA/TEF is 1% suggesting many result from de novo mutations and while environmental factors may have a minor influence, the mechanisms are unclear. The investigators hypothesize that patients diagnosed with TED and similar disorders carry distinct mutations that lead to predisposition. Currently the diagnosis is confirmed only with a plain chest x-ray showing a coiled feeding tube within the upper esophageal pouch. This approach does not determine the anatomic subtype of EA/TEF, the number or location of TEFs, the size of the gap between proximal and distal esophagus, or the presence of tracheomalacia. Many have evaluated preoperative laryngotracheo-bronchoscopy (LTB) and others have evaluated preoperative computerized tomography (CT) scanning to decrease the unknown factors associated with x-ray, but despite their potential benefits, they have great drawbacks. Therefore, there is a compelling need to develop noninvasive non ionizing imaging methods to evaluate TED infants. Magnetic Resonance Imaging (MRI) is an ideal candidate to fill this role in that it provides non-invasive high resolution anatomic and functional information. Here the investigators propose a preliminary study performing exome sequencing on samples from these patients and their biologically related family members. The investigators will also use advanced, non-invasive MR imaging techniques to assess TE, lung, and cardiac morphology and function in NICU patients.

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Study Type : Observational
Estimated Enrollment : 260 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Comprehensive Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
Actual Study Start Date : March 28, 2018
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2024


Group/Cohort
NICU TED Genetic Cohort
This study involves one inpatient biofluid collection encounter from the subject, one biofluid collection encounter from each biological parent, and an optional biofluid collection encounter from other biological family members.
NICU TED MRI Cohort
This study involves up to three inpatient NICU MRI encounters. The first MRI may be done before surgical repair if the clinical team feels the infant is clinically stable. The second MRI may be completed post-surgical repair of TED. An additional 3rd MRI may be done prior to the time of discharge from the NICU. The pre repair, post-surgical, and pre discharge MRIs will provide valuable data for the understanding of tracheal esophageal malformation disorders and may provide clinical guidance for the participant's care.
TED Genetic Cohort
This study involves one biofluid collection encounter from the subject, one biofluid collection encounter from each biological parent, and an optional biofluid collection encounter from other biological family members.
NICU Control MRI Cohort
This study involves two inpatient NICU MRI encounters. The first MRI will occur within the first month of life, and the second MRI will occur prior to discharge.



Primary Outcome Measures :
  1. Genomic Sequencing [ Time Frame: 1 day ]
    Identify novel genes and mutations in patients with TEDs using trio genomic sequencing of TED patients and their parents.

  2. Anatomic phenotypes using MRI [ Time Frame: 1 day ]
    Investigate the esophageal, tracheal, mediastinal and pulmonary anatomy in patients with TEDs.


Secondary Outcome Measures :
  1. Change in the anatomic phenotype using MRI [ Time Frame: Change in MRI from pre-repair to discharge ]
    Investigate the esophageal, tracheal, mediastinal and pulmonary anatomy in patients with TEDs before and after surgical repair.


Biospecimen Retention:   Samples With DNA
Biofluids, such as, blood and/or salvia and surgical tissue samples


Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Approximately 100 NICU TED patient/parent trios for the NICU TED Genetic cohort.

Approximately 100 NICU TED patients for the NICU TED MRI cohort. These patients will also be in the NICU TED cohort.

Approximately 155 TED patient/parent trios from the Esophageal Center for the Esophageal Center Genetic cohort.

Approximately 5 NICU infants with normal tracheal and esophageal anatomy for the NICU Control MRI cohort.

Criteria

NICU TED Genetic Cohort:

Inclusion Criteria:

  • Infant born between 24 and 42 weeks PMA.
  • TED diagnosed by clinical team.
  • Inpatient in the Neonatal Intensive Care Unit (NICU) OR family member to the inpatient in the NICU.
  • Willingness to donate biological specimens.
  • Ability to consent/assent as appropriate.

Exclusion Criteria:

  • Unable to determine or unavailable parent trio.
  • Unable to provide DNA sample.
  • Inability to provide consent.

NICU TED MRI Cohort:

Inclusion Criteria:

  • Infant born between 24 and 42 weeks PMA.
  • TED diagnosed by clinical team.
  • Inpatient in the CCHMC (Cincinnati Children's Hospital Medical Center) NICU.
  • Clinically stable and adequate temperature control to tolerate MRI as determined by the primary clinical team.
  • Infant and biological parents are participating in the NICU TED cohort.
  • Ability to consent/assent as appropriate.

Exclusion Criteria:

  • Infant is on extracorporeal membrane oxygenation (ECMO).
  • Evidence of congenital diseases that may affect ability to tolerate MRI.
  • Standard MRI exclusion criteria as set forth by the CCHMC Department of Radiology. This includes any contraindications from tracheostomy tubes that are not MR compatible.
  • Inability to provide consent.

TED Genetic Cohort:

Inclusion Criteria:

  • Patient that has been diagnosed by clinical team with a congenital TED OR family member to the TED diagnosed patient.
  • Willingness to donate biological specimens.
  • Ability to consent/assent as appropriate.

Exclusion Criteria:

  • Unable to determine or unavailable parent trio.
  • Unable to provide DNA sample.
  • Inability to provide consent.

NICU Control MRI Cohort:

Inclusion Criteria:

  • Infant born between 24 and 42 weeks post menstrual age (PMA).
  • No tracheal or esophageal defects.
  • Inpatient in the CCHMC NICU.
  • Clinically stable and adequate temperature control to tolerate MRI as determined by the primary clinical team.

Exclusion Criteria:

  • Infant is on ECMO.
  • Evidence of congenital diseases that may affect ability to tolerate MRI.
  • Standard MRI exclusion criteria as set forth by the CCHMC Department of Radiology. This includes any contraindications from tracheostomy tubes that are not MR compatible.
  • Inability to provide consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03455881


Contacts
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Contact: Paul Kingma, MD, PhD (513)636-2995 paul.kingma@cchmc.org

Locations
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United States, Ohio
Cincinnati Children's Hospital Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Paul Kingma, MD, PhD    513-636-2995    paul.kingma@cchmc.org   
Principal Investigator: Paul Kingma, MD, PhD         
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Columbia University
Investigators
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Principal Investigator: Paul Kingma, MD, PhD Children's Hospital Medical Center, Cincinnati

Publications:

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Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT03455881     History of Changes
Other Study ID Numbers: CIN_PhenoandGeneticTED_001
1P01HD093363-01 ( U.S. NIH Grant/Contract )
First Posted: March 7, 2018    Key Record Dates
Last Update Posted: March 21, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Children's Hospital Medical Center, Cincinnati:
TEF
EA
Tracheal Esophageal birth Defect (TED)
Additional relevant MeSH terms:
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Esophageal Atresia
Tracheoesophageal Fistula
Airway Obstruction
Tracheal Stenosis
Congenital Abnormalities
Constriction, Pathologic
Fistula
Pathological Conditions, Anatomical
Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Digestive System Abnormalities
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Tracheal Diseases
Esophageal Fistula
Digestive System Fistula
Respiratory Tract Fistula