Improving Right Ventricular Function in Young Adults Born Preterm

Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study

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

Study Overview

• Status: Completed
• Conditions: Infant,Premature
• Intervention / Treatment: Procedure: Pulmonary Function Testing; Procedure: Electrocardiogram; Procedure: Cardiac Magnetic Resonance Imaging; Drug: Metoprolol; Drug: Sildenafil

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 Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin-Madison School of Medicine and Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sildenafil followed by 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.	Procedure: Pulmonary Function Testing; Subjects will undergo spirometry, Plethysmography, and diffusion capacity.; Procedure: Electrocardiogram; Subjects will undergo an electrocardiogram to ensure sinus rhythm; Procedure: Cardiac Magnetic Resonance Imaging; Subjects will undergo positron magnetic resonance imaging to detect images of the heart; Drug: Metoprolol; Subjects will receive intravenous metoprolol. Dose titrated 1-5 mg every 2 minutes to achieve goal heart rate of 55-65 beats per minute, or for subjects with a resting heart rate already at goal, titrated to achieve a 10-15% reduction in heart rate.; Other Names: Lopressor; Metolar XR; Drug: Sildenafil; Subjects will receive a 50 milligram tablet of sildenafil (to be taken orally); Other Names: Revatio
Experimental: Metoprolol followed by 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.	Procedure: Pulmonary Function Testing; Subjects will undergo spirometry, Plethysmography, and diffusion capacity.; Procedure: Electrocardiogram; Subjects will undergo an electrocardiogram to ensure sinus rhythm; Procedure: Cardiac Magnetic Resonance Imaging; Subjects will undergo positron magnetic resonance imaging to detect images of the heart; Drug: Metoprolol; Subjects will receive intravenous metoprolol. Dose titrated 1-5 mg every 2 minutes to achieve goal heart rate of 55-65 beats per minute, or for subjects with a resting heart rate already at goal, titrated to achieve a 10-15% reduction in heart rate.; Other Names: Lopressor; Metolar XR; Drug: Sildenafil; Subjects will receive a 50 milligram tablet of sildenafil (to be taken orally); Other Names: Revatio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Right Ventricular Energetic Efficiency Pre and Post Metoprolol	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.	up to 2 hours
Right Ventricular Energetic Efficiency Pre and Post Sildenafil	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.	up to 2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular Energetic Efficiency Pre and Post Metoprolol	Kinetic energy (from 4D flow) normalized to ventricular volume (from MRI). Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Right Ventricular Ejection Fraction Pre and Post Metoprolol	Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Right Ventricular Stroke Volume Pre and Post Metoprolol	Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Right Ventricular Systolic Volume Pre and Post Metoprolol	Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Right Ventricular Diastolic Volume Pre and Post Metoprolol	Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Left Ventricular Ejection Fraction Pre and Post Metoprolol	Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Left Ventricular Stroke Volume Pre and Post Metoprolol	Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Left Ventricular Systolic Volume Pre and Post Metoprolol	Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Left Ventricular Diastolic Volume Pre and Post Metoprolol	Participants will receive intravenous metoprolol in between scans.	up to 2 hours
Left Ventricular Energetic Efficiency Pre and Post Sildenafil	Kinetic energy (from 4D flow) normalized to ventricular volume (from MRI). Participants will be given sildenafil in between imaging scans.	up to 2 hours
Right Ventricular Ejection Fraction Pre and Post Sildenafil	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.	up to 2 hours
Right Ventricular Stroke Volume Pre and Post Sildenafil	Participants will be given sildenafil in between imaging scans.	up to 2 hours
Right Ventricular Systolic Volume Pre and Post Sildenafil	Participants will be given sildenafil in between imaging scans.	up to 2 hours
Right Ventricular Diastolic Volume Pre and Post Sildenafil	Participants will be given sildenafil in between imaging scans.	up to 2 hours
Left Ventricular Ejection Fraction Pre and Post Sildenafil	Participants will be given sildenafil in between imaging scans.	up to 2 hours
Left Ventricular Stroke Volume Pre and Post Sildenafil	Participants will be given sildenafil in between imaging scans.	up to 2 hours
Left Ventricular Systolic Volume Pre and Post Sildenafil	Participants will be given sildenafil in between imaging scans.	up to 2 hours
Left Ventricular Diastolic Volume Pre and Post Sildenafil	Participants will be given sildenafil in between imaging scans.	up to 2 hours

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Kara N Goss, MD, University of Wisconsin-Madison School of Medicine and Public Health

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2018
• Primary Completion (Actual): February 24, 2020
• Study Completion (Actual): February 24, 2020

Study Registration Dates

• First Submitted: October 3, 2018
• First Submitted That Met QC Criteria: October 3, 2018
• First Posted (Actual): October 5, 2018

Study Record Updates

• Last Update Posted (Actual): March 17, 2021
• Last Update Submitted That Met QC Criteria: February 24, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: MRI; sildenafil; premature; CMR; metoprolol; premature adults; premature cardiac function
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Metoprolol
• Other Study ID Numbers: 2018-0796; A534285 (Other Identifier: UW Madison); 1UL1TR002373-01 (U.S. NIH Grant/Contract); SMPH/MEDICINE/PULMON MED (Other Identifier: UW, Madison); Protocol Version 8/30/2018 (Other Identifier: UW Madison)

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No