Improving Right Ventricular Function in Young Adults Born Preterm

Phase 2

Completed

• Conditions: Infant,Premature
• Interventions: Procedure: Pulmonary Function Testing; Procedure: Electrocardiogram; Procedure: Cardiac Magnetic Resonance Imaging; Drug: Metoprolol; Drug: Sildenafil

• Registration Number: NCT03696758
• Lead Sponsor: University of Wisconsin, Madison

Brief Summary

The purpose of this research is to evaluate the short-term effects of sildenafil and metoprolol on heart function in young adults born premature.

Detailed Description

The purpose of this study is to evaluate the short-term therapeutic effects of sildenafil and metoprolol on right ventricular function in young adults born premature using novel 4-Dimensional flow Cardiac Magnetic Resonance Imaging.

Study Timeline

• Study First Submitted: 2018-10-03
• Study First Submitted QC: 2018-10-03
• Study First Posted: 2018-10-05
• Study Start: 2018-10-30
• Primary Completion: 2020-02-24
• Study Completion: 2020-02-24
• Results First Submitted: 2021-01-14
• Status Verified: 2021-02
• Results First Submitted QC: 2021-02-22
• Last Update Submitted: 2021-02-24
• Results First Posted: 2021-02-25
• Last Update Posted: 2021-03-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

1. Provision of signed and dated informed consent form

2. Male or female aged 18-35

3. History of preterm birth (either a or b):

   1. Participant in the Newborn Lung Project (birth year 1988-1991, birth weight <1500 g)
   2. Non-NLP participant, with birth weight <1500 g and gestational age 32 weeks or less, verified by medical records

Exclusion Criteria

1. Pregnant or lactating

2. Use of prescribed medications that would interfere with study medications

   1. Sildenafil: Use of phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil), nitrates, soluble guanylate cyclase inhibitor (riociguat) within 48 hours of study visit
   2. Metoprolol: Use of nodal blocking agents including beta blockers, non-dihydropyridine calcium channel blockers (i.e. diltiazem), and anti-arrhythmics (i.e. amiodarone)

3. Presence of known comorbidities for which these therapeutic interventions would be contraindicated:

   1. Moderate to severe heart failure
   2. Severe bradycardia (heart rate <45), or second or third-degree heart block
   3. Systolic blood pressure <90 mmHg or >190 mmHg
   4. Angina
   5. Severe peripheral arterial circulatory disorders
   6. History of severe bronchospasm

4. Presence of any implanted device incompatible with CMR imaging

5. Known allergic or hypersensitivity reaction to components of the study medications

6. Any other reason for which the investigator deems a subject unsafe or inappropriate for study participation.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sildenafil followed by Metoprolol	Cardiac Magnetic Resonance Imaging	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given sildenafil in between imaging scans at one visit, and will receive intravenous metoprolol in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Metoprolol followed by Sildenafil	Pulmonary Function Testing	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given metoprolol in between imaging scans at one visit, and will receive intravenous sildenafil in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Metoprolol followed by Sildenafil	Electrocardiogram	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given metoprolol in between imaging scans at one visit, and will receive intravenous sildenafil in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Sildenafil followed by Metoprolol	Electrocardiogram	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given sildenafil in between imaging scans at one visit, and will receive intravenous metoprolol in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Sildenafil followed by Metoprolol	Pulmonary Function Testing	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given sildenafil in between imaging scans at one visit, and will receive intravenous metoprolol in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Metoprolol followed by Sildenafil	Cardiac Magnetic Resonance Imaging	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given metoprolol in between imaging scans at one visit, and will receive intravenous sildenafil in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Sildenafil followed by Metoprolol	Sildenafil	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given sildenafil in between imaging scans at one visit, and will receive intravenous metoprolol in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Sildenafil followed by Metoprolol	Metoprolol	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given sildenafil in between imaging scans at one visit, and will receive intravenous metoprolol in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Metoprolol followed by Sildenafil	Metoprolol	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given metoprolol in between imaging scans at one visit, and will receive intravenous sildenafil in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.
Metoprolol followed by Sildenafil	Sildenafil	Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given metoprolol in between imaging scans at one visit, and will receive intravenous sildenafil in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram.

Primary Outcome Measures

Name	Time	Method
Right Ventricular Energetic Efficiency Pre and Post Metoprolol	up to 2 hours	To characterize energy efficiency, the total Kinetic Energy across the cardiac cycle is normalized to right ventricular end-diastolic volume and left ventricular end-diastolic volume, respectively. Analysis will be completed in blinded fashion. Two imaging scans will be done - one pre and one post Metoprolol intervention. Total time from Pre-intervention scan till post intervention scan may take up to 2 hours.
Right Ventricular Energetic Efficiency Pre and Post Sildenafil	up to 2 hours	To characterize energy efficiency, the total Kinetic Energy across the cardiac cycle is normalized to right ventricular end-diastolic volume and left ventricular end-diastolic volume, respectively. Analysis will be completed in blinded fashion. Two imaging scans will be done - one pre and one post Sildenafil intervention. Total time from Pre-intervention scan till post intervention scan may take up to 2 hours.

Secondary Outcome Measures

Name	Time	Method
Left Ventricular Stroke Volume Pre and Post Metoprolol	up to 2 hours	Participants will receive intravenous metoprolol in between scans.
Left Ventricular Diastolic Volume Pre and Post Metoprolol	up to 2 hours	Participants will receive intravenous metoprolol in between scans.
Right Ventricular Ejection Fraction Pre and Post Sildenafil	up to 2 hours	Participants will be given sildenafil in between imaging scans. The term "ejection fraction" refers to the percentage of blood that's pumped out of a filled ventricle with each heartbeat.
Right Ventricular Stroke Volume Pre and Post Metoprolol	up to 2 hours	Participants will receive intravenous metoprolol in between scans.
Right Ventricular Systolic Volume Pre and Post Metoprolol	up to 2 hours	Participants will receive intravenous metoprolol in between scans.
Left Ventricular Ejection Fraction Pre and Post Metoprolol	up to 2 hours	Participants will receive intravenous metoprolol in between scans.
Left Ventricular Systolic Volume Pre and Post Metoprolol	up to 2 hours	Participants will receive intravenous metoprolol in between scans.
Left Ventricular Energetic Efficiency Pre and Post Metoprolol	up to 2 hours	Kinetic energy (from 4D flow) normalized to ventricular volume (from MRI). Participants will receive intravenous metoprolol in between scans.
Right Ventricular Ejection Fraction Pre and Post Metoprolol	up to 2 hours	Participants will receive intravenous metoprolol in between scans.
Right Ventricular Stroke Volume Pre and Post Sildenafil	up to 2 hours	Participants will be given sildenafil in between imaging scans.
Right Ventricular Systolic Volume Pre and Post Sildenafil	up to 2 hours	Participants will be given sildenafil in between imaging scans.
Right Ventricular Diastolic Volume Pre and Post Metoprolol	up to 2 hours	Participants will receive intravenous metoprolol in between scans.
Left Ventricular Energetic Efficiency Pre and Post Sildenafil	up to 2 hours	Kinetic energy (from 4D flow) normalized to ventricular volume (from MRI). Participants will be given sildenafil in between imaging scans.
Left Ventricular Ejection Fraction Pre and Post Sildenafil	up to 2 hours	Participants will be given sildenafil in between imaging scans.
Left Ventricular Systolic Volume Pre and Post Sildenafil	up to 2 hours	Participants will be given sildenafil in between imaging scans.
Right Ventricular Diastolic Volume Pre and Post Sildenafil	up to 2 hours	Participants will be given sildenafil in between imaging scans.
Left Ventricular Diastolic Volume Pre and Post Sildenafil	up to 2 hours	Participants will be given sildenafil in between imaging scans.
Left Ventricular Stroke Volume Pre and Post Sildenafil	up to 2 hours	Participants will be given sildenafil in between imaging scans.

Trial Locations

Locations (1)

University of Wisconsin-Madison School of Medicine and Public Health; 🇺🇸 Madison, Wisconsin, United States