Genetic Regulation of Surfactant Deficiency

June 4, 2021 updated by: Washington University School of Medicine

Genetic Regulation of Surfactant Deficiency in Human Newborn Infants

Inherited deficiencies in any one of 3 genes (surfactant protein B, surfactant protein C, and ATP-binding cassette transporter A3) can cause neonatal respiratory distress syndrome by disrupting metabolism of the pulmonary surfactant. The investigators will use state of the art methods to link specific changes in the genetic code of each of these genes with disruption of discrete steps in the metabolism of the pulmonary surfactant in human newborn infants. These studies will lead to improved diagnostic capabilities and suggest novel strategies to correct surfactant deficiency in newborn infants.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Genetic regulation of neonatal pulmonary surfactant deficiency has been suggested by studies of gender, genetic linkage, recurrent familial cases, targeted gene ablation in murine lineages, and by racial disparity in risk of neonatal respiratory distress syndrome. Successful fetal-neonatal pulmonary transition requires production of the pulmonary surfactant, a phospholipid-protein film that lines alveoli and maintains alveolar patency at end expiration. Our goal is to understand the genetic mechanisms that disrupt pulmonary surfactant metabolism and cause neonatal respiratory distress syndrome. Studies in human newborn infants have demonstrated that 3 genes are critical for surfactant metabolism: surfactant protein B (SFTPB), surfactant protein C (SFTPC), and an ATP-binding cassette transporter, ABCA3 (ABCA3). To understand genetic regulatory mechanisms, we will investigate the contribution of variation in each of these genes to risk of neonatal respiratory distress syndrome by testing the hypothesis that genetic variants in the SFTPB, SFTPC, and ABCA3 disrupt pulmonary surfactant metabolism. Using high throughput automated sequencing to genotype, multidimensional protein identification technology to assess quantitative and qualitative differences in surfactant protein B and C expression, in vivo metabolic labeling with stable isotopically labeled precursors to estimate surfactant protein B and C and phospholipid metabolic rates, and cohort sizes that provide statistical power (0.8), we will use race-specific, severity-stratified case-control (N=480) and case comparison (N=250) designs to understand genetically regulated, metabolic mechanisms that cause surfactant deficiency by disrupting expression or altering processing of surfactant proteins B or C or by disrupting surfactant phospholipid composition in human newborn infants. Improved understanding of genetic regulation of surfactant deficiency will suggest novel diagnostic strategies to identify and categorize high risk infants and therapeutic strategies that target discrete steps in pulmonary surfactant metabolism to improve outcomes of infants with neonatal respiratory distress syndrome.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
525

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • St. Louis Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

1 day to 6 months (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The study population includes infants with and without neonatal respiratory distress syndrome (N=513) and infants with varying severity of neonatal respiratory distress syndrome (N=12).

Description

Inclusion Criteria:

  • Newborn infants with respiratory distress syndrome who require mechanical ventilation via endotracheal tube or tracheostomy in the first 6 months of life

Exclusion Criteria:

  • Infants with conditions likely to cause imminent death

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Genetic association
Infants with and without neonatal respiratory distress syndrome undergo surfactant gene sequencing to identify genomic variants associated with neonatal respiratory distress syndrome
Nutrient
To newborn infants with respiratory distress syndrome, we administer stable isotopically labeled nutrients (precursors of surfactant phospholipids or proteins) to permit mass spectrometry-based comparison of surfactant phospholipid and protein turnover.
Drug: Nutrient
We administer stable isotopically labeled precursors of surfactant phospholipids ([1-13C1] acetate) and of surfactant protein-B ([5,5,5-2H3] leucine) to infants with neonatal respiratory distress syndrome. Using mass spectrometry, we measure incorporation of stable isotopically labeled precursors in tracheal aspirates and compare surfactant phospholipid and surfactant protein-B turnover.
Other Names:
  • [1-13C1] acetate, [5,5,5-2H3] leucine

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Association of specific variants or interactions among variants in SFTPB, SFTPC, and ABCA3 with neonatal respiratory distress syndrome
Time Frame: 1 week
Statistical association of increased risk of neonatal respiratory distress in term or near term infants with specific genomic variants in SFTPB, SFTPC, and ABCA3
1 week

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Association of specific variants or interactions among variants in SFTPB, SFTPC, and ABCA3 with fractional synthetic rate and/or fractional catabolic rate of surfactant phospholipids, surfactant protein-B, and surfactant protein-C
Time Frame: 1 week
Statistical association of quantitative surfactant phospholipid metabolic characteristics with specific genomic variants in SFTPB, SFTPC, and ABCA3
1 week

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Washington University School of Medicine

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: F. S. Cole, M.D., Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2007

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2013

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2013

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 22, 2009

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 22, 2009

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 23, 2009

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 7, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 4, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 07-0156
  • R01HL082747 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

Enter discovered genomic variants in dbGaP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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