EU-IPFF committed to promoting research in Pulmonary Fibrosis

Pulmonary Vascular Disease in CF

Study Purpose

In this project, the investigators seek to understand the role of endothelial cells in Cystic Fibrosis (CF) lung disease. This objective will be achieved by conducting a cross sectional clinical study to define the morphology of the pulmonary circulation across a range of lung function coupled with a mechanistic study of the effect of dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) in endothelial cells on vasculogenesis, epithelial morphogenesis and epithelial CFTR function. Toward that end, the investigators propose the following hypotheses; (a). Loss of pulmonary small blood vessels begins early in the CF lung and worsens with disease progression, (b).VEGFR2-CFTR interactions happen at the plasma membrane of endothelial cells and is likely to be involved in transendothelial ion transport (c) impaired VEGFR2-CFTR interactions on the endothelial cells will have a profound effect on vasculogenesis, epithelial morphogenesis and ion transport. The first hypotheses will be tested through this clinical study. The following 2 hypotheses will be tested through laboratory studies that do not involve human subjects.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Observational
Eligible Ages	5 Years - 21 Years
Gender	All

More Inclusion & Exclusion Criteria

Cystic Fibrosis Patients:

Inclusion Criteria:

- 5-21 years of age.

- diagnosis of CF based on a positive sweat test and genetic testing.

- Baseline pulmonary condition defined as a) Absence of signs and symptoms of pulmonary exacerbation, b) Baseline pulmonary function test (PFT) defined as FEV1% that is no less than 5% of the best PFT in the previous 6 months, c) Patients should be off acute antibiotics for 2 weeks or longer.

- Subjects should be able to perform an acceptable and reproducible spirometry.

- Study population will be equally divided between three groups based on FEV1%, (FEV1% ≥ 90); moderate (60 ≤ FEV1% < 90)
Exclusion Criteria:
- Enrollment in clinical trials of CFTR correctors and or potentiator.

- Enrollment in gene therapy trial.

- Pregnancy.

Historical Controls.

Inclusion Criteria:

- solid tumor diagnosis.

- had chest CT scan to survey possible metastasis or any other lung disease.

- age and gender matched to Cystic Fibrosis patients

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04549077
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Children's Hospital Medical Center, Cincinnati
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Cystic Fibrosis

Additional Details

Pulmonary disease in Cystic Fibrosis (CF) is characterized by progressive loss of functional gas exchange units that eventually results in respiratory failure. In CF lung disease, remodeling of pulmonary blood vessels, and vascular growth of bronchial blood vessels leading to systemic vascularization of the lung are the principal characteristics of pulmonary vascular disease. Studies have demonstrated that abnormal perfusion is present in up to 85% of 1 year old CF infants and only 17% of the perfusion deficits could be explained by mucus plugging or bronchial wall abnormalities at this age. Based on the investigators' state of the art method to reconstruct the pulmonary vasculature from non-contrast high resolution CT scan of the lungs, the investigators demonstrated that the blood volume in small vessels begins to decline when lung function is still in the normal range and worsens with increase disease severity. Furthermore, the investigators have also demonstrated that systemic vascularization of the lungs by the bronchial circulation begins at a FEV1% of 100. Preclinical studies of pulmonary endothelium revealed that delivering vascular endothelial growth factor receptor (VEGFR) antagonist to rats leads to air space enlargement and pruning of the pulmonary arterial tree. Thus, there is a central unanswered question as to whether pulmonary vascular disease (vascular remodeling and systemic vascularization) are just a squeal of parenchymal destruction or whether they contribute to the loss of alveolar gas exchange units and decline in lung function. In this proposal, the investigators will accomplish the following aims: 1) describe the morphology of the pulmonary vasculature across a wide range of lung function and relate the findings to functional outcomes, 2) examine mechanism of early loss of small blood vessels in CF patients as it relates to endothelial CFTR dysfunction. In addition, the investigators will study the changes in the pulmonary circulation after the initiation of triple combination therapy Trikafta (elexacaftor, ivacaftor, and tezacaftor). This is a case control study of 93 cystic fibrosis patients and 100 age and gender matched controls. CF patients (cases) will be recruited from two cystic fibrosis centers, Cincinnati Children's Hospital and Riley Children's Hospital. Controls will be subjects from the oncology service without lung disease who had CT scan of the chest to rule out pulmonary metastasis. 31 subjects of the 93 subjects enrolled will receive a second evaluation 6 months after starting a clinically prescribed corrector / modulator of Cystic Fibrosis Transmembrane Conductance Protein Regulator (Trikafta) that was approved by the FDA in October, 2019 for patients with CF ages 12 and up. If FDA approval for use of Trikafta for ages 6-11 years of age is obtained, this patient age range will also be eligible for the second evaluation at 6 months.

Arms & Interventions

Arms

: Cystic Fibrosis Patients

Patients with Cystic Fibrosis.

: Historical Controls

Patients diagnosed with solid tumors, who have had a normal chest CT scan during screening for possible metastasis

Interventions

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Riley Hospital for Children, Indianapolis, Indiana

Status

Recruiting

Address

Riley Hospital for Children

Indianapolis, Indiana, 46204-3509

Site Contact

James F. Chmiel, MD

[email protected]

317-948-7208

Cincinnati, Ohio

Status