Assessment of the TGF-beta Pathway and Micro-RNA in Pediatric Pulmonary Arterial Hypertension

November 12, 2021 updated by: Edward Kirkpatrick, Medical College of Wisconsin
This is a prospective pilot study to assess the plasma levels of particular proteins involved in the transforming growth factor beta (TGF-β) pathway and its down stream regulators, CHIP, as well as micro RNA molecules in subjects with pulmonary arterial hypertension (PAH) and compare them to control subjects without PAH to see if they can be used as a diagnostic or prognostic marker of PAH and how this compares to other diagnostic biomarkers N-terminal pro-natriuretic peptide (NT Pro-BNP) and C-reactive protein (CRP).

Study Overview

Status

Status

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

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

Aim 1: This study will correlate proteins in the TGF- β signaling pathway and micro RNA levels with invasive (catheterization) and non-invasive (echocardiography) measurements of pulmonary artery pressures to assess for the presence and severity of PAH and compare these measurements to the established biomarkers of NT Pro BNP and CRP levels.

Hypothesis 1: Plasma levels of proteins of the TGF-β pathway; bone morphogenic protein (BMP) 2, 4, 6, 7, 9 and 10 along with activin A and TGF-β1 protein as well as CHIP (carboxyl-terminus of Hsp70-intracting protein), an enzyme that regulates the activations and exports of TGF- β to the nucleus will be significantly different in subjects with PH over control subjects.

Hypothesis 2: Plasma levels of proteins in the TGF- β pathway; BMP 2, 4, 6, 7, 9 and 10 along with activin A and TGF-β1 protein as well as CHIP will show better correlation with the presence of PAH and its severity than NT-Pro BNP and CRP levels.

Hypothesis 3: The micro-RNA profiles in plasma will be significantly different in subjects with PAHPH over control subjects.

Aim 2: To correlate protein/micro-RNA levels with clinical status in PAH subjects as assessed by functional status, exercise testing, and PAH drug regimen to determine if they can correlate with disease severity.

Hypothesis 1: Clinical findings in PAH patients will correlate with disease severity and study proteins and micro-RNA levels better than established biomarkers.

Aim 3: To correlate evidence of genetic abnormalities through whole exome sequencing especially in regions known or suspected to cause PAH (e.g. BMPR2, ENG, and ALK1 mutations), within the TGF-β pathway or lung development with the tested protein/micro-RNA levels.

Hypothesis 1: Genetic evaluation of patients with PAH will show abnormalities within the TGF-β pathway or lung development.

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 (Anticipated)

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.
40

Contacts and Locations

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

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Recruiting
        • Children's Hospital of Wisconsin
        • Contact:
        • Contact:

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

2 years to 17 years (Child)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Subjects with previously confirmed or suspected to have pulmonary arterial hypertension (PAH) that are undergoing a clinically indicated cardiac catheterization (for diagnostic evaluation) ages 2-17 years are eligible for participation.

Control subjects undergoing a catheterization as part of an intervention such as atrial septal defect closure or patent ductus arteriosus closure and have a routine right heart catheterization as a part of that procedure and meet inclusion criteria.

Description

Inclusion Criteria:

  • Pediatric subjects ages 2-17 years
  • Subjects undergoing a clinically indicated cardiac catheterization.
  • Subjects with proven or being evaluated for pulmonary hypertension in WHO classification group 1 or 3†
  • Subjects will be categorized as PAH subjects if they meet the hemodynamic criteria: pulmonary artery pressure >20mmHg, pulmonary vascular resistance index >3 Woods units*m2, and wedge pressures <15mmHg.
  • Subjects can be categorized as control subjects if they do not have PH on catheterization and do not meet any exclusion criteria.

Exclusion Criteria:

-

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.
PH subjects
  • Pediatric subjects ages 2-17 years
  • Subjects undergoing a clinically indicated cardiac catheterization.
  • Subjects with proven or being evaluated for pulmonary hypertension in WHO classification group 1 or 3†
  • Subjects will be categorized as PAH subjects if they meet the hemodynamic criteria: pulmonary artery pressure >20mmHg, pulmonary vascular resistance index >3 Woods units*m2, and wedge pressures <15mmHg.
Diagnostic test: Protein Elisa analysis, microRNA analysis, whole exome sequencing

ELISA Testing Procedure: The circulating levels of BMP 2, 4, 6, 7, 9 and 10, together with activin A and TGF-β as well as CHIP will be measured using streptavidin ELISA assays.

Micro-RNA analysis: From 100µL of plasma, we will prepare small RNA libraries using TruSeq Small RNA Sample Preparation kit (Illumina Inc).

TGF-B mutation evaluation: Blood from subjects with PH will also be analyzed for known genetic mutations in TGF-B pathway using whole exome sequencing.
Control subjects
  • Pediatric subjects ages 2-17 years
  • Subjects undergoing a clinically indicated cardiac catheterization.
  • Subjects can be categorized as control subjects if they do not have PH on catheterization and do not meet any exclusion criteria.
Diagnostic test: Protein Elisa analysis, microRNA analysis, whole exome sequencing

ELISA Testing Procedure: The circulating levels of BMP 2, 4, 6, 7, 9 and 10, together with activin A and TGF-β as well as CHIP will be measured using streptavidin ELISA assays.

Micro-RNA analysis: From 100µL of plasma, we will prepare small RNA libraries using TruSeq Small RNA Sample Preparation kit (Illumina Inc).

TGF-B mutation evaluation: Blood from subjects with PH will also be analyzed for known genetic mutations in TGF-B pathway using whole exome sequencing.

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
Plasma levels of BMP proteins of the TGF-β pathway
Time Frame: One day
bone morphogenic protein (BMP) 2, 4, 6, 7, 9 and 10 levels will be obtained in PH subjects and will be compared to control subjects in effort to describe how those levels are different in subjects with PH over control subjects. All measured amounts of proteins will be in pg/ml.
One day
Plasma Activin A and TGF-β1 level of the TGF-β pathway
Time Frame: One day
Activin A and TGF-β1 plasma levels will be obtained in PH subjects and compared to control subjects in effort to describe how those levels are different in subjects with PH over control subjects. All measured amounts will be will be in pg/ml.
One day
Plasma CHIP levels assessment in PH patients and control subjects.
Time Frame: One day
CHIP (carboxyl-protein terminus of Hsp70-intracting protein) plasma levels will be obtained in PH subjects and compared to control subjects in effort to describe how those levels are different in subjects with PH over control subjects. All measured levels will be in pg/ml
One day

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
Plasma levels of proteins in the TGF- β pathway and PH disease severity
Time Frame: One day
BMP 2, 4, 6, 7, 9 and 10 along with activin A and TGF-β1 protein as well as CHIP levels will be correlated with the presence of PAH and its severity and how that compares to the levels of NT-Pro BNP and CRP levels.
One day
MicroRNA levels in PH vs control subjects
Time Frame: One day
The micro-RNA profiles in plasma will be compared between in subjects with PAH and control subjects.
One day
Clinical findings correlation with study proteins/microRNA
Time Frame: One day
Clinical findings in PAH patients will be correlated with disease severity and study protein and micro-RNA levels.
One day
Whole exome sequence analysis in PH patients and protein/microRNA levels
Time Frame: One day
To correlate evidence of genetic abnormalities through whole exome sequencing especially in regions known or suspected to cause PAH (e.g. BMPR2, ENG, and ALK1 mutations), within the TGF-β pathway or lung development with the tested protein/micro-RNA levels.
One day

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.
Medical College of Wisconsin

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: Edward C Kirkpatrick, Children's Hospital and Health System Foundation, Wisconsin

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 (Actual)

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.
July 1, 2020

Primary Completion (Anticipated)

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.
August 1, 2022

Study Completion (Anticipated)

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.
January 1, 2023

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).
July 21, 2020

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.
July 23, 2020

First Posted (Actual)

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.
July 28, 2020

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.
November 22, 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.
November 12, 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.
November 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.
  • 1492809

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

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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