Conditions: Infant,Premature
Keywords: premature adults premature premature cardiac function MRI sildenafil metoprolol CMR
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 10
Healthy volunteers: no

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Pulmonary Function Testing intervention 2: Electrocardiogram intervention 3: Cardiac Magnetic Resonance Imaging intervention 4: Metoprolol intervention 5: Sildenafil
Intervention descriptions: intervention 1: Subjects will undergo spirometry, Plethysmography, and diffusion capacity. intervention 2: Subjects will undergo an electrocardiogram to ensure sinus rhythm intervention 3: Subjects will undergo positron magnetic resonance imaging to detect images of the heart intervention 4: 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. intervention 5: Subjects will receive a 50 milligram tablet of sildenafil (to be taken orally)

Protocol document:
Prot_SAP_000.pdf: 
 
Improving Right Ventricular Function in Young Adults Born 
Preterm: A Pilot Study 
NCT03696758 
08/30/2018 
 
 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
1 
 
Protocol Title:  
Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
 
Protocol Number:  
2018-0796 
 
National Clinical Trial Identified Number:  
NCT03696758 
 
Principal Investigator:  
Kara Goss, MD 
 
Sponsor:  
Kara Goss, MD 
 
Funded by:  
UW Institute for Clinical and Translational Research 
 
Version Number:  
V1, Aug 30 2018 
 
 
 
Statement of Compliance:  
 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), 
and the Sponsor Terms and Conditions of Award. The Principal Investigator will assure that no 
deviation from, or changes to the protocol will take place without prior agreement from the 
Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor, funding 
agency and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP Training.  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 
 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
2 
 
Table of Contents 
1. PROTOCOL SUMMARY 
5 
1.1 Synopsis 
5 
1.2 Schema 
6 
2. INTRODUCTION 
8 
2.1 Study Rationale: 
8 
2.2 Background: 
8 
2.3 Risk/benefit Assessment: 
8 
2.3.1 Known Potential Risks: 
8 
2.3.2 Known Potential Benefits: 
10 
2.3.3 Assessment of Potential Risks and Benefits: 
11 
3. OBJECTIVES AND ENDPOINTS 
11 
4. STUDY DESIGN 
11 
4.1 Overall Design 
11 
4.2 Scientific Rationale for Study Design 
12 
4.3 Justification for Dose 
12 
4.4 End of Study Definition 
12 
5. STUDY POPULATION 
13 
5.1 Inclusion Criteria 
13 
5.2 Exclusion Criteria 
13 
5.3 Lifestyle Considerations 
13 
5.4 Screen Failures 
14 
6. STUDY INTERVENTION 
15 
6.1 Study Intervention(s) Administration 
15 
6.1.1 Study Intervention Description 
15 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
3 
 
6.1.2 Dosing and Administration 
15 
6.2 Preparation/Handling/Storage/Accountability 
15 
6.2.1 Acquisition and Accountability 
15 
6.2.3 Product Storage and Stability 
15 
6.2.4 Preparation 
16 
6.4 Study Intervention Compliance 
16 
6.5 Concomitant Therapy 
16 
6.5.1 Rescue Medicine: not applicable 
16 
7. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
 
16 
7.1 Discontinuation of Study Intervention 
16 
7.2 Participant Discontinuation/Withdrawal from the Study 
16 
7.3 Lost to Follow Up 
17 
8. STUDY ASSESSMENTS AND PROCEDURES 
17 
8.1 Efficacy Assessments 
17 
8.2 Safety and Other Assessments 
18 
8.3 Adverse Events and Serious Adverse Events 
19 
8.3.1 Definition of Adverse Events (AE) 
19 
8.3.2 Definition of Serious Adverse Events (SAE) 
19 
8.3.3 Classification of an Adverse Event 
20 
8.3.3.1 Severity of Event 
20 
8.3.3.2 Relationship to Study Intervention 
20 
8.3.3.3 Expectedness 
20 
8.3.4 Time Period and Frequency for Event Assessment and Follow Up 
20 
8.3.5 Adverse Event Reporting 
21 
8.3.6 Serious Adverse Event Reporting 
21 
8.3.7 Reporting Events to Participants 
21 
8.3.8 Events of Special Interest 
22 
8.3.9 Reporting of Pregnancy 
22 
8.4 Unanticipated Problems 
22 
8.4.1 Definition of Unanticipated Problems (UP) 
22 
8.4.2 Unanticipated Problem Reporting 
22 
8.4.3 Reporting Unanticipated Problems to Participants 
23 
9. STATISTICAL CONSIDERATIONS 
23 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
4 
 
9.1 Statistical Hypothesis 
23 
9.2 Sample Size Determination 
23 
9.3 Populations for Analyses 
23 
9.4 Statistical Analyses 
23 
9.4.1 General Approach 
23 
9.4.2 Analysis of the Primary Efficacy Endpoint 
23 
9.4.3 Analysis of the Secondary Endpoint(s) 
24 
9.4.4 Safety Analyses 
24 
9.4.5 Baseline Descriptive Statistics 
24 
9.4.6 Planned Interim Analysis 
24 
9.4.7 Sub-group Analysis 
24 
9.4.8 Tabulation of Individual Participant Data 
24 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
24 
10.1 Regulatory, Ethical and Study Oversight Considerations 
24 
10.1.1 Informed Consent Process 
24 
10.1.1.1 Consent/Assent and Other Informational Documents Provided to Participants 
24 
10.1.1.2 Consent Procedures and Documentation 
24 
10.1.2 Study Discontinuation and Closure 
25 
10.1.3 Confidentiality and Privacy 
26 
10.1.5 Key Roles and Study Governance 
26 
10.1.6 Safety Oversight 
27 
10.1.7 Clinical Monitoring - Not applicable: internal safety and data oversight 
27 
10.1.8 Quality Assurance and Quality Control 
27 
10.1.9 Data Handling and Record Keeping 
27 
10.1.9.1 Data Collection and Management Responsibilities 
27 
10.1.9.2 Study Records Retention 
27 
10.1.10 Protocol Deviations 
28 
10.1.11 Publication and Data Sharing Policy 
28 
10.1.12 Conflict of Interest Policy 
28 
10.2 Additional Considerations 
29 
11. REFERENCES 
29 
 
 
 
 
 
 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
5 
 
1. Protocol Summary 
 
1.1 Synopsis 
 
Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
 
Study description: Adults born premature have smaller, less efficient hearts as demonstrated 
by recent cardiac magnetic resonance (CMR) imaging. The goal of this proposal is to assess the 
impact of pharmacologic reduction of right ventricular (RV) afterload and resting heart rate on RV 
energetic inefficiency in young adults born premature using novel 4D flow CMR imaging. 
 
Objectives: 
 
Aim 1: Evaluate the effect of acute right ventricular (RV) afterload reduction with sildenafil 
on RV function and energetic efficiency in young adults born premature. In addition to being a 
potent pulmonary vasodilator, several studies suggest that sildenafil may have direct inotropic 
and/or lusitropic effects on the RV. We hypothesize that sildenafil will reduce afterload and 
improve RV diastolic function, thereby improving RV function and energetic efficiency, as 
assessed by cardiac MRI (CMR) with 4D flow. 
 
Aim 2: Assess the effect of acute beta blockade with metoprolol on RV function and 
energetic efficiency in young adults born premature. We have recently identified that adolescents 
and adults born premature have increased resting heart rates and autonomic dysfunction. We 
hypothesize that beta blockade with metoprolol will improve RV filling time and therefore improve 
function and energetic efficiency, as assessed by CMR and 4D flow. 
 
Endpoints:  
 
Primary endpoint: RV energetic efficiency. Energetic efficiency is defined as the kinetic 
energy (work) required for a given stroke volume in the heart, expressed as mL/mJ. Kinetic 
energy is measured using novel 4D flow imaging to assess flow velocities through the heart, 
which are then summed across the cardiac cycle. Stroke volume is calculated based on the end 
diastolic volume minus the end systolic volume.  
 
Secondary endpoints: LV energetic efficiency, RV ejection fraction, stroke volume, and 
end systolic/diastolic volumes, LV ejection fraction, stroke volume, and end systolic/diastolic 
volumes. 
 
The same endpoints will be used in both therapeutic interventions above, with 
comparison of efficacy of each intervention.  
 
Study population:  
 
Preterm subjects will be recruited from the Newborn Lung Project or the local population. 
Those identified from the Newborn Lung Project (NLP) cohort were born preterm from 1988-
1991, birth weight <1500g, average gestational age 28 weeks, and have been prospectively 
followed since enrollment. Preterm subjects recruited outside the NLP will be aged 18-35, with a 
birth weight <1500 g OR gestational age of 32 weeks or less. Birth history for non-NLP subjects 
will be confirmed from health records. 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
6 
 
Recruitment will include both male and female subjects of any race/ethnicity. Subjects 
must not be pregnant or lactating and may not be prescribed any other cardiac medications that 
would interact with the proposed therapeutic interventions (i.e. nitrates contraindicated with 
sildenafil, nodal-blocking agents contraindicated with metoprolol). Proposed sample size for pilot 
study is 10 subjects. 
 
Phase: 2 
 
Description of sites/facilities: University of Wisconsin 
 
Description of study intervention:  
 
Subjects will present for two imaging visits, with a single drug administered during each 
study day. Subjects will undergo CMR scanning with acquisition of standard measures of cardiac 
function sequences as well as 4D flow before and after therapeutic dosing, as described below 
(see Figure 1 for overall study design). Order of drug dosing may be reversed.  
During study visit #1, young adults born preterm will complete two CMR with 4D flow 
scans. Subjects will be monitored with continuous EKG and pulse oximetry during scanning, with 
blood pressure measures taken at least every 10 minutes. After completion of the first resting 
scan with image acquisition as described above, subjects will be administered metoprolol IV. 
Dosing will be titrated (1-5 mg Q2 min) to achieve a resting heart rate of 55-65. For subjects with 
a resting heart rate already within range, a 10-15% reduction in heart rate will be targeted. 
Subjects will then undergo a second CMR with 4D flow. Subjects will be monitored for side effects 
from metoprolol, including bradycardia, dizziness, and hypotension. 
During study visit #2, young adults born preterm will complete two CMR with 4D flow 
scans. Subjects will be monitored with continuous EKG and pulse oximetry during scanning, with 
blood pressure measures taken at least every 10 minutes. After completion of the first resting 
scan with image acquisition as described above, subjects will be administered sildenafil 50 mg 
orally. Prior studies demonstrate that sildenafil reaches peak hemodynamic effect in 
approximately 50 minutes after oral intake, and its biological effects last for at least 3 hours.1,2 
One hour after oral administration of sildenafil, subjects will complete a second CMR with 4D flow. 
Subjects will be monitored for side effects from sildenafil, including flushing, headache, and 
hypotension. Sildenafil has been safely used even in advanced heart failure patients, and thus 
we expect this medication to be well tolerated.  
Blood and urine will be obtained during the initial visit for biobanking. The blood sample 
will be less than 80 mL. Biobanking is not optional for the study. Samples will be coded so that 
they can be linked back to data obtained in the study, including MRI data, pulmonary function 
data, and birth records. Samples will be stored in a locked laboratory and used exclusively for 
research purposes to learn more about the effects of premature birth on heart and lung function. 
Samples will be used primarily by the study investigators but may be shared with researchers 
outside of the University of Wisconsin. The identify codes not be shared beyond the investigators 
in this study. Participants will not receive results of any research tests using banked samples. 
 
Study duration: 18 months 
 
Participant duration: Each visit is estimated to take 2-3 hours. 
 
1.2 Schema 
 
 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
7 
 
 
 
1.3 Schedule of activities 
 
 
Procedures 
Phone Screening 
Enrollment/Baseline^  
(may be combined with 
study visit 1 procedures) 
Study Visit 1^  
(administration of metoprolol 
or sildenafil) 
Study Visit 2 
(administration of metoprolol 
or sildenafil) 
Review study requirements and eligibility 
X 
 
 
 
Informed consent 
 
X 
 
 
Demographics 
 
X 
 
 
Medical history 
 
X 
 
 
Vitals 
 
X 
 
AN 
Height 
 
X 
 
AN 
Weight 
 
X 
 
AN 
EKG 
 
X 
 
 
Pulmonary function 
 
X 
 
 
Pregnancy test (*women only) 
 
X 
 
 
Urine collection for biobanking 
 
X 
 
 
Blood for biobanking (*obtained at time of IV placement) 
 
 
X* 
X* 
Baseline cardiac MRI with 4D flow 
 
 
X 
X 
Medication administration 
 
 
X 
X 
Post-intervention cardiac MRI with 4D flow 
 
 
X 
X 
 
 
 
 
 
 
AN Vitals, Height, and Weight will be repeated if Visit 2 occurs >7 days after Visit 1 
* Blood for biobanking will be obtained either at Visit 1 or Visit 2, but not both. 
^ Enrollment/Baseline and Visit 1 will most likely occur on the same day/visit. However, subjects can 
choose to complete these visits on separate days.  


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
8 
 
 
2. Introduction 
 
2.1 Study Rationale:  
 
Moderate to extreme preterm birth is associated with a 3-5 fold increased risk for 
development of pulmonary hypertension and up to a 17 fold increased risk for heart failure. We 
have identified early cardiac energetic inefficiency using cardiac 4D flow measures. The goal of 
this proposal is to assess the impact of pharmacologic reduction of right ventricular (RV) afterload 
and resting heart rate on RV energetic inefficiency in young adults born premature using novel 
4D flow cardiac magnetic resonance imaging. 
 
2.2 Background: 
 
Preterm birth, defined as less than 37 weeks completed gestation, affects one in 10 live 
births in the United States.3 In 2017, the NIH recommended that premature birth be considered a 
chronic medical disease due to its long-lasting multi-system effects.4,5 While lung disease is the 
most frequently recognized complication of prematurity, adults born moderately to extremely 
preterm have a 3-fold increased risk for the development of pulmonary and systemic 
hypertension, and a 17-fold increased risk for heart failure.6-8 Young adults born premature have 
biventricular hypertrophy, though the right ventricle (RV) is disproportionately affected, with 
functional impairments in RV but not left ventricular (LV) ejection fraction in early adulthood.9-12 
This relationship has significant clinical relevance since RV dysfunction and failure are associated 
with increased mortality regardless of the etiology.13-15 However, the mechanisms of RV 
dysfunction in this population are poorly understood, and may have unique implications for 
treatment considerations. 
The University of Wisconsin has recruited a rare cohort of approximately 265 young adults 
born premature between 1988-1991, prospectively followed as part of the Newborn Lung Project 
(NLP).16-18 Our recent work in this cohort demonstrates that young adults born premature have 
lower exercise tolerance,19 early pulmonary vascular disease, and impaired cardiac reserve. 
Novel 4D cardiac flow imaging demonstrates a higher kinetic work for a given stroke volume in 
young adults born premature, representing a decreased cardiac energetic efficiency that may 
predispose to heart failure. Intriguingly, using a rodent model of premature birth, we have also 
demonstrated early pulmonary vascular disease yet ‘out-of-proportion’ RV dysfunction that 
emerges when animals are aged to 1 year, despite no further deterioration in afterload or 
elevations of pulmonary pressures.20-22 When applied to our human cohort, this paradox suggests 
that development of overt pulmonary hypertension may not be required for the RV to fail, and is 
in stark contrast to current RV failure paradigms. Therefore, there is a critical need to understand 
the direct RV effects of cardiac therapeutics in high-risk young adults born premature, as currently 
there are no RV-specific therapeutics for the treatment of pulmonary hypertension or RV failure. 
The goal of this proposal is to assess the impact of pharmacologic reduction of RV afterload and 
resting heart rate on RV energetic inefficiency in young adults born premature using novel 4D 
flow cardiac magnetic resonance (CMR) imaging. 
 
2.3 Risk/benefit Assessment: 
 
 
2.3.1 Known Potential Risks:  
 
MRI: The standard risks associated MRI involve persons with certain metallic implants 
and devices (eg. pacemakers), and claustrophobia. Those patients eligible for study participation 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
9 
 
will be screened for contraindicated metallic foreign bodies and claustrophobia using standard 
clinical exclusionary procedures on our MRI safety screening form. No gadolinium will be 
administered, which eliminates the concern of contrast induced reactions.  
Electronic implants, such as cardiac pacemakers, may be susceptible to interference from 
the magnetic and RF fields produced by the MR system. This interference may destroy or 
negatively affect operation of these devices. The magnetic field of the MR system exerts a force 
on ferromagnetic objects within the field. This force can cause a ferromagnetic implant, such as 
an aneurysm clip, surgical clip, or prosthesis, to move or be displaced and cause injury or death. 
If the implant is large, sufficient currents can be induced in the metal by the magnetic field (eddy 
currents are induced by pulsed gradient fields) to cause heating of the implant. It is possible that 
subtle genetic or molecular changes could be caused by the magnetic fields produced by the MR 
system. To date, however, no harmful biological effects have been demonstrated at the magnetic 
field strengths and exposure times utilized by the MR system. At the present time, the likelihood 
of any significant biomagnetic effect is considered to be very low. The magnetic field near the MR 
system is strong enough to attract ferromagnetic objects with great force. Near the magnet this 
force can be strong enough to pull objects in and cause them to fly down the axis of the magnet. 
Such objects become projectiles that can cause injury or death. 
 
Pulmonary function testing: Risks associated with the pulmonary function testing include 
shortness of breath, dizziness, and cough. If they occur, they are expected to resolve after 
completion of testing.  
 
EKG: Risks associated with EKG include discomfort or contact dermatitis from the 
adhesive used to adhere the leads.  
 
Venipuncture: Risks associated with venipuncture are limited to slight pain, bleeding, 
bruising, and swelling at the puncture site. Some subjects may feel lightheaded during the 
procedure. IV catheter placement: may cause pain, bruising, fainting or infection. Topical 
anesthetic creams may be used to lessen the pain. With placement of the IV catheter, there is a 
rare risk (less than 1 out of 100 people) of bleeding, or infection associated with placement of the 
plastic tube in the vein. 
 
Fasting: Risks associated with an overnight fast (minimum 8 hour) fast are minimal. 
Subjects may feel weak, lightheaded, or lethargic. Individuals accustomed to drinking caffeinated 
beverages may experience headaches. Subjects will be encouraged to drink plenty of water 
during this time and to notify a study team member if they need to stop the fast. 
 
Metoprolol: Reported adverse reactions include (2-15% in chronic dosing): bradycardia, 
hypotension, heart block, heart failure, hypertension, angina, fatigue, dizziness, shortness of 
breath, bronchospasm, hypersensitivity reactions, diarrhea. Effects of acute one-time dosing are 
expected to be limited to hemodynamic effects. Subjects will be monitored with continuous EKG, 
continuous pulse oximetry, and cycled blood pressure (every 10 minutes) to minimize potential 
for adverse reaction. Furthermore, dose of metoprolol will be titrated to desired effect (goal heart 
rate 55-65 or 10-15% reduction in heart rate). Full prescribing information from package insert 
can be found at:  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017963s062,018704s021lbl.pdf.  
 
Sildenafil: Reported adverse reactions include (2-46% in chronic dosing): headache, 
flushing, upset stomach, diarrhea, shortness of breath, runny nose/sinus congestion. Rare 
adverse events (<2% in chronic dosing) include visual disturbances and prolonged erection in 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
10 
 
males.  Effects of acute one-time dosing are expected to be minimal. Subjects will be monitored 
with continuous EKG, continuous pulse oximetry, and cycled blood pressure (every 10 minutes) 
to minimize potential for adverse reaction. Full prescribing information from package insert can 
be found at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020895s033lbl.pdf.  
 
Risk of Embarrassment: Persistent erection is a potential side effect of sildenafil, although 
occurring in <2% of males. If a male subject experiences this side effect, it’s possible they could 
feel uncomfortable or embarrassed.  
 
Questionnaires: Risks associated with questionnaires include subject fatigue and feeling 
uncomfortable. 
 
Breach of confidentiality: There is a risk of breach of confidentiality. In order to protect 
against this risk, all data will be stored on a secure, password protected network. All data will be 
identified using unique identification numbers, not names, date of birth, or other identifiable 
information. In files where identifiable information is linked to the unique ID number, only staff 
members who specifically use this information for contacting participants, etc. will have access.  
All CMR scans performed for research purposes only will be given a unique study number that 
cannot be linked to the patients’ hospital medical records in any way. CMR research images will 
be stored on PACS (Picture Archiving and Communication System) under this study number only.  
Study data will be managed by the PI and co-investigators. 
 
Recruitment database: Participants may opt-in or opt-out for participation in a recruitment 
database. Study data will be included as part of this database, and participants may be 
recontacted for future studies based on data retained within the database. This data may include 
information from the phone screen, study visits & procedures, and NLP or neonatal records. Only 
research staff will have access to the information. There is a very small chance or breach of 
confidentiality (see above). This database will be maintained by the PI, and stored using the same 
confidentiality protections described throughout the study. 
 
Biobanking: Blood and urine will be obtained during the initial visit for biobanking. 
TSamples will be coded so that they can be linked back to data obtained in the study, including 
MRI data, pulmonary function data, and birth records. Samples will be stored in a locked 
laboratory and used exclusively for research purposes to learn more about the effects of 
premature birth on heart and lung function. Samples will be used primarily by the study 
investigators but may be shared with researchers outside of the University of Wisconsin. The 
identify codes not be shared beyond the investigators in this study. Participants will not receive 
results of any research tests using banked samples. 
 
Possible future genetic research: Future work with biobanked samples may include 
genetic research. Subjects may opt-in or opt-out of future genetic research, though biobanking 
is not optional. Future research involving large-scale genomic data may be subject to the NIH 
Genomic Data Sharing policy, and will comply with all applicable current regulatory 
requirements. This will be addressed as (1) part of any future protocols that involved large-scale 
genomic research using specimens collected on this study, or (2) a change of protocol under 
the current study to address GDS policy requirements on behalf of the researchers who conduct 
genetic analysis. 
 
 
 
2.3.2 Known Potential Benefits:  


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
11 
 
 
 
 
Subjects are not expected to receive any immediate benefit from the study procedures. 
However, improving our long-term understanding of prematurity associated cardiomyopathy 
may have a direct impact on our understanding of treatment needs for both individual 
participants as well as individuals with a history of premature birth at large.  
 
 
2.3.3 Assessment of Potential Risks and Benefits:  
 
 
Overall, the study procedures are noninvasive aside from placement of an intravenous 
catheter. The study medications have a long history of tolerability in both healthy subjects as 
well as patients with even advanced heart failure and are expected to be well tolerated for acute 
dosing in this population. Subjects will be monitored closely for development of treatment-
associated adverse events.  
 
3. Objectives and Endpoints 
 
Objectives 
Endpoints 
Justification 
Primary 
 
 
Improve RV function 
RV kinetic energy efficiency* 
RV energy efficiency is reduced in 
preterm-born subjects, and is 
suspected to be an early marker of 
heart failure; improvement in RV 
energy efficiency may decrease heart 
failure risk 
Secondary 
 
 
Improve LV function 
LV kinetic energy efficiency* 
To be most effective, a therapeutic 
intervention needs to improve both 
RV and LV efficiency/function 
Assess standard 
measures of RV 
function 
RV ejection fraction, stroke 
volume, and end 
systolic/diastolic volumes 
These are standard measures of 
cardiac function, but change later 
than energy efficiency measures 
Assess standard 
measures of LV 
function 
LV ejection fraction, stroke 
volume, and end 
systolic/diastolic volumes 
These are standard measures of 
cardiac function, but change later 
than energy efficiency measures 
 
* Energetic efficiency is defined as the kinetic energy (work) required for a given stroke volume 
in the heart, expressed as mL/mJ. Kinetic energy is measured using novel 4D flow imaging to 
assess flow velocities through the heart, which are then summed across the cardiac cycle. 
Stroke volume is calculated based on the end diastolic volume minus the end systolic volume.  
 
4. Study Design 
 
4.1 Overall Design 
 
Hypothesis:  
 
1. Sildenafil will reduce afterload and improve RV diastolic function, thereby improving RV 
function and energetic efficiency, as assessed by CMR with 4D flow 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
12 
 
2. Beta blockade with metoprolol will improve RV filling time and therefore improve function 
and energetic efficiency, as assessed by CMR and 4D flow 
 
Phase:  2 
 
Type of trial: Cross-over design pilot study 
 
Methods to minimize bias: To minimize bias, we will utilize clearly defined outcomes (i.e. RV 
energy efficiency as primary). Eligibility, including history of preterm birth, will be confirmed in all 
subjects. The study will be registered at clinicaltrials.gov. 
 
Study groups:  All subjects will be adults born premature. Subjects will participate in a cross-
over design study, where their responses to two therapeutic interventions are compared.  
 
Site(s): University of Wisconsin 
 
Study Interventions: sildenafil, metoprolol 
 
4.2 Scientific Rationale for Study Design 
 
 
This study will utilize a cross-over design to study the acute effects of two different 
classes of cardiac medications on cardiac performance. Prematurity associated cardiomyopathy 
is a newly described cardiomyopathy characterized by biventricular right greater than left 
hypertrophy found in neonates, children, and adults born premature. Our preliminary work 
demonstrates a biventricular impairment in cardiac energy efficiency, as well as elevations in 
pulmonary pressures. The biventricular dysfunction mandates added therapeutic considerations 
given that drugs targeting LV dysfunction may be harmful to the RV and vice versa. Here, we 
will utilize two treatment strategies – pulmonary vasodilation to reduce RV afterload and beta-
blockade to improve filling time to assess the effects on biventricular function using 4D flow 
CMR imaging protocols. 
 
4.3 Justification for Dose 
 
 
Sildenafil is a pulmonary vasodilator. Subjects will be administered sildenafil 50 mg 
orally. Prior studies demonstrate that sildenafil reaches peak hemodynamic effect in 
approximately 50 minutes after oral intake, and its biological effects last for at least 3 hours.1,2 
This dose has previously been well tolerated in both healthy subjects and in patients with heart 
failure. 
 
Metoprolol is a beta-blocker, with primary cardiac effect of slowed heart rate. Subjects 
will be administered metoprolol IV. Dosing will be titrated (1-5 mg Q2 min) to achieve a resting 
heart rate of 55-65. For subjects with a resting heart rate already within range, a 10-15% 
reduction in heart rate will be targeted, with the goal of improving cardiac filling time which may 
lead to improved cardiac filling time and cardiac energy efficiency. 
 
4.4 End of Study Definition 
 
 
A participant is considered to have completed the study if he or she completed all 
phases of the study including the final scheduled visit/procedure shown in the Schedule of 
Activities. The end of the study is defined as completion of the last visit or procedure shown in 
the Schedule of Activities in the trial globally.  


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5. Study Population 
 
5.1 Inclusion Criteria 
 
 
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria:  
1. Provision of signed and dated informed consent form 
2. Male or female aged 18-35 
3. History of preterm birth: 
a. Participant in the Newborn Lung Project (birth year 1988-1991, birth 
weight <1500 g) 
b. Non-NLP participant, with birth weight <1500 g and gestational age 32 
weeks or less, verified by medical records 
 
5.2 Exclusion Criteria 
 
 
An individual who meets any of the following criteria will be excluded from participation in 
the study:  
 
1. Pregnant or lactating 
2. Use of prescribed medications that would interfere with study medications  
a. Sildenafil: Use of phosphodiesterase type 5 inhibitors (sildenafil, 
tadalafil, vardenafil), nitrates, soluble guanylate cyclase inhibitor 
(riociguat) within 48 hours of study visit 
b. 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: 
a. Moderate to severe heart failure 
b. Severe bradycardia (heart rate <45), or second or third-degree heart 
block 
c. Systolic blood pressure <90 mmHg or >190 mmHg 
d. Angina 
e. Severe peripheral arterial circulatory disorders 
4. History of severe bronchospasmPresence 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. 
 
5.3 Lifestyle Considerations 
 
 
During this study, participants are asked to: 
 
 
Abstain from caffeine and alcohol for 24 hours prior to each imaging study. 
 
Avoid grapefruit consumption for 48 hours prior to imaging study 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
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 
Fast for a minimum of 8 hours prior to the study visit involving lab draw for 
biobanking. 
 
Fast for a minimum of 4 hours prior to the study visit involving oral sildenafil 
administration. 
 
Subjects unable to meet these restrictions may be excluded from the study or may have 
their visits rescheduled for a different time when they can better meet the restrictions 
(investigator discretion).  
 
5.4 Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered into the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). Individuals who do not meet the criteria 
for participation in this trial (screen failure) because of a specific modifiable factor may be 
rescreened. Rescreened participants should be assigned the same participant number as for 
the initial screening. 
 
5.5 Strategies for Recruitment and Retention 
 
Pilot study target sample size: 10 completed subjects (not including screen failures) 
 
Anticipated accrual rate: 1 subject per month 
 
Number of sites: 1 
 
Source of participants:  
 
 
Newborn Lung Project.  
 
General public with verified history of premature birth. 
 
Subject identification and recruitment:  
 
Preterm subjects who have previously participated in research conducted in the Eldridge 
laboratory or by Dr. Kara Goss (IRB 2009-0212, 2013-1523, and 2017-0238) and who have 
previously given consent for contact will be recruited for participation. We have mailing addresses, 
email addresses, and phone numbers for these members of the NLP cohort. Using contact 
information provided by the subjects for re-contact, potential subjects from the NLP cohort will 
receive a recruitment email, letter, or phone call, asking if they would like to be part of the study. 
Subjects will not be contacted more than 3 times total by any single method if we don't receive a 
response. Messages left on phones will not include health information. If the subject is not 
reached, the message will give our contact information for them to call back.  
Recruitment of non-NLP preterm subjects from the general public will be done via: 
 
Mass mailing (ie through UW email) 
 
Posting local flyers (ie UW Hospitals and Clinics approved message boards) or via 
paid newspaper advertisements 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
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 
Through internet posting (ie posting on social media sites, UW Facebook Research 
pages, Jobcenter board, or Craiglist Madison).  
Interested individuals will contact the study coordinator. Women and minorities will be recruited, 
with a goal to have equal distribution of sexes. Given the small initial study size, minority ethnic 
groups will not be directly targeted but will be welcomed. 
 
Compensation:  
 
$450 for completion of all study visits. Parking validation and travel expenses (ie mileage) will be 
provided for research subjects. Compensation may be prorated at $50/hr if a subject is unable to 
complete the visit. 
 
6. Study Intervention 
 
6.1 Study Intervention(s) Administration 
 
  
 
6.1.1 Study Intervention Description 
 
Both study drugs (sildenafil and metoprolol) are commercially available and will be used 
in accordance with approved labeling.  
Metoprolol: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017963s062,018704s021lbl.pdf.  
Sildenafil:  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020895s033lbl.pdf.  
 
 
6.1.2 Dosing and Administration 
 
Metoprolol: IV, 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. 
  
Sildenafil: 50 mg oral once 
 
6.2 Preparation/Handling/Storage/Accountability 
 
 
6.2.1 Acquisition and Accountability 
 
 
Study medications will be acquired from the University of Wisconsin Pharmaceutical 
Research Center (PRC). All unused medications will be returned to the PRC.  
 
 
 
6.2.2 Formulation, Appearance, Packaging and Labeling 
 
 
Medications will be packaged in standard clinical packaging, concentration of 5 mg/5ml.  
 
 
6.2.3 Product Storage and Stability 
 
 
Medications will be retained in original packaging/carton until time of use, and protected 
from light.  
 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
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6.2.4 Preparation 
 
 
Metoprolol will be drawn into a syringe for administration by an appropriately 
credentialed team member (RN or MD) by IV push. Saline flush will be administered after each 
dose.  
 
No special preparation concerns for sildenafil. 
 
 
6.3 Measures to Minimize Bias 
 
 
Study interventions are not blinded. There will be a minimum period of 12 hours between 
drug interventions to ensure adequate drug wash-out. 
 
6.4 Study Intervention Compliance 
 
All study medications will be administered in a clinical setting to ensure compliance.  
 
 
6.5 Concomitant Therapy 
 
Use of concomitant medications will be assessed at the baseline visit. Medications to be 
reported in the Case Report Form are concomitant prescription medications, over-the-counter 
medications, and supplements.  
 
 
6.5.1 Rescue Medicine: not applicable 
 
7. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
 
 
7.1 Discontinuation of Study Intervention 
 
 
 
Participants may withdraw voluntarily from the study or the PI may discontinue a 
participant from the study. The UW IRB approved consent form will state that subjects may 
withdraw from this study at any time without any change in the quality of their medical care or 
loss of benefits.  
 
7.2 Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request.  
An investigator may discontinue or withdraw a participant from the study for the following 
reasons:  
• Pregnancy  
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best interest of 
the participant  
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation  
• Participant unable to receive the study intervention  
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form and are enrolled but do 
not receive the study intervention may be replaced. Subjects who sign the informed consent 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
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form, and are enrolled and receive the study intervention, and subsequently withdraw, or are 
withdrawn or discontinued from the study, will be replaced. 
 
7.3 Lost to Follow Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 1 visit and 
is unable to be contacted by the study site staff. The following actions must be taken if a 
participant fails to return to the clinic for a required study visit:  
• The site will attempt to contact the participant and reschedule the missed visit and 
ascertain if the participant wishes to and/or should continue in the study.  
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record or 
study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8. Study Assessments and Procedures 
 
8.1 Efficacy Assessments 
 
Cardiac Imaging: CMR will be performed on a 3T scanner (GE Healthcare, Waukesha, 
WI). The CMR protocol, including sequences and analyses, is summarized in Table 1. 
Multiplanar, cardiac gated, cine balanced steady-state free precession (bSSFP) series will be 
acquired through the heart for assessment of heart size and function. Flow through the tricuspid 
and mitral valves will be assessed with cardiac gated, cine two-dimensional (2D) flow-sensitive 
sequences. Four-dimensional flow sensitive magnetic resonance imaging (4D flow MRI) will be 
performed with a radial undersampled acquisition, Phase Contrast with Vastly undersampled 
Isotropic Projection Reconstruction (PC VIPR).32-34 CMR sequence parameters will be individually 
adapted to each participant’s anatomy to optimize scan time and temporal resolution as 
recommended by the Society of Cardiovascular Magnetic Resonance.35 
Cardiac MRI Analysis: Standard CMR images will be analyzed per published 
recommendations.36 Analysis will be conducted by the University of Wisconsin Medical Imaging 
Research Support-Image Analysis Core. Outcomes determined will include measures of RV and 
LV cardiac systolic and diastolic function (Table 1). Assessment of systolic function will include 
quantification of RV and LV end-diastolic volume index, end systolic volume index, stroke volume 
index, ejection fraction, cardiac output, and cardiac index. Peak filling rate and time to peak filling 
rate, indices of diastolic function, will be determined by segmentation of the RV and LV throughout 
the cardiac cycle. Diastolic function will also be evaluated by quantifying the peak transtricuspid 
and transmitral valve velocities during ventricular relaxation (E-wave velocity) and atrial 
contraction (A-wave velocity), as well as their ratio (E/A).  
4D Flow Analysis: Ventricular kinetic energy (KE), main pulmonary artery (MPA) flow and 
ascending aorta flow will be quantified from the 4D flow MRI data using previously published 
algorithms developed at our institution.33,34 Briefly, the heart and thoracic vasculature will be 
segmented from the complex difference angiographic images using commercial image 
processing software (Mimics, Materialise, Leuven, Belgium) and exported as a mask to be 
combined with the time-resolved three-directional velocity data within a visualization software 
package (Ensight, CEI Inc., Apex, NC). Flow in the MPA and ascending aorta will be measured 


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from planes 2 cm from the annulus. RV and LV KE is determined by independently segmenting 
each of the ventricles from time-averaged PC VIPR magnitude images in Mimics. A mask is 
applied to the time-resolved velocity images, and the kinetic energy across the cardiac cycle is 
computed using the formula: KEtotal=frame voxel∑1  ½ mv2, where m=mass and v=velocity. To 
characterize energy efficiency, the total KE across the cardiac cycle is normalized to the flow 
through the MPA (QP) and aorta (QS).   
 
Table 1. CMR protocol for assessment of RV and LV systolic and diastolic function, 
efficiency and fibrosis. 
Ventricle 
Assessment 
MRI sequence(s) 
Measurements 
RV 
Systolic function 
Axial cine bSSFP 
EDVi, ESVi, SVi, EF, CO, CI 
Diastolic function 
Axial cine bSSFP 
2D flow (tricuspid valve) 
PFR, TTPFR 
E, A, E/A 
Efficiency 
4D flow MRI 
KE, MPA flow 
LV 
Systolic function 
Short axis cine bSSFP 
EDVi, ESVi, SVi, EF, CO, CI 
Diastolic function 
Short axis cine bSSFP 
2D flow (mitral valve) 
IVRT 
E, A, E/A 
Efficiency 
4D flow MRI 
KE, aorta flow 
Abbreviations – bSSFP, balanced steady state free precession; 2D, two-dimensional; 4D, four-
dimensional; EDVi, end-diastolic volume index; ESVi, end-systolic volume index; SVi; stroke 
volume index; EF, ejection fraction; CO, cardiac output; CI, cardiac index; PFR, peak filling rate; 
TTPFR, time to peak filling rate; E, peak flow velocity during ventricular relaxation; A, peak flow 
velocity during atrial contraction; KE, kinetic energy; MPA, main pulmonary artery. 
 
8.2 Safety and Other Assessments 
 
Screening: Study coordinators will conduct a phone screen to determine eligibility.  
 
Verification of medical records: General information regarding birth history will be asked 
of all subjects (i.e. gestational age, birth weight). This history will be verified and additional birth 
history will be collected from Newborn Lung Project medical records, records from previous 
studies that collected NLP data (IRB 2009-0212, 2013-1523, and/or 2017-0238), or birth 
hospitals, where available. This information will include prenatal characteristics (including but not 
limited to: maternal age, demographics, gravidity, comorbidities such as diabetes, hypertension, 
asthma, tobacco use, alcohol use, antenatal steroid use), birth and postnatal characteristics 
(including but not limited to: gestational age, anthropometric data, delivery type, and data 
regarding neonatal comorbidities such as bronchopulmonary dysplasia, intracardiac shunts, 
sepsis, respiratory failure, nutrition), and childhood characteristics (including but not limited to: 
anthropometric data, history of early wheezing, cigarette exposure, treatment for respiratory 
illnesses such as bronchopulmonary dysplasia and asthma, and serial pulmonary function 
testing). 
 
Baseline measures: Study coordinators will verify demographic and medical history data 
with subjects. An MRI metal screening sheet will be completed in accordance with standard 
clinical practice. Anthropometric measures (height, weight) and vital signs (heart rate, 
respiratory rate, pulse ox, blood pressure) will be obtained in accordance with standard clinical 
practice. If the CMR imaging visits are separated by >7 days, anthropometric and vital sign 
measures will be repeated.  
 


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Pregnancy testing: All female participants will complete a urine pregnancy test. If the 
CMR imaging visits are separated by >7 days, a repeat pregnancy test will be required.  
 
EKG: All subjects will undergo a resting EKG for screening purposes to verify absence of 
severe bradycardia or heart block prior to proceeding to imaging. EKGs will be reviewed by a 
qualified study personnel at the time they are completed. Abnormal findings that would exclude 
participation will be discussed with the study participant immediately. Devices are non-
investigational.  
 
Pulmonary function testing: Subjects will undergo non-invasive pulmonary function testing 
including spirometry, plethysmography (for lung volumes) and diffusion capacity, according to 
standard clinical testing. All procedures are performed according to standard clinical practice and 
all devices are non-investigational. 
 
Venous cannulation: One intravenous (IV) line will be placed by qualified study personnel. 
Lidocaine or topical anesthetic may be administered as a local anesthetic.  
 
Biospecimens for biobanking: Blood for biobanking will be collected at the time of IV 
placement. Blood volume sampled will be less than 80 ml total. Urine samples will be collected 
for biobanking at the baseline visit.   
 
Health questionnaires: The subjects will answers health questionnaires, a Pre-Session 
Questionnaire and Symptom Questionnaire. 
 
Monitoring during CMR: Subjects will be monitored with continuous EKG and pulse 
oximetry during scanning, with blood pressure measures taken at least every 10 minutes. 
Subjects will be assessed for adverse events during and after therapeutic intervention. 
 
Incidental Findings: Testing that excludes a subject from study participation (i.e. positive 
pregnancy test, second or third-degree heart block) will be disclosed immediately. EKG and 
pulmonary function testing will be reviewed by the study team, and any potentially clinically 
significant abnormal findings will be discussed with subjects by a qualified RN or MD on the study 
team. Clinically significant non-investigational CMR findings will be discussed with subjects by a 
qualified MD on the study team. 
 
8.3 Adverse Events and Serious Adverse Events 
 
 
8.3.1 Definition of Adverse Events (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
Anticipated day-to-day fluctuations of the disease under study that do not represent a clinically 
significant exacerbation or worsening do not need to be considered an adverse event, unless 
they: 
 
1. fulfill the definition of a serious adverse event, or 
 
2. have worsened and are clinically significant requiring medical intervention other than the 
use of the rescue medication, or 
 
3. result in discontinuation of subject from the study. 
 
 
 
8.3.2 Definition of Serious Adverse Events (SAE) 


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An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the 
view of the PI, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse 
 
 
8.3.3 Classification of an Adverse Event 
 
 
 
 
8.3.3.1 Severity of Event 
 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.  
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”.  
 
 
 
 
8.3.3.2 Relationship to Study Intervention 
 
All adverse events (AEs) must have their relationship to study intervention assessed by 
the clinician who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect.  
Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship between 
the study intervention and event. Reasonable possibility means that there is evidence to 
suggest a causal relationship between the study intervention and the AE.  
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established.  
 
8.3.3.3 Expectedness 
 
The PI will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study intervention. 
 
 
8.3.4 Time Period and Frequency for Event Assessment and Follow Up 
 


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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to 
the attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor.  
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution.  
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
A study coordinator will record all reportable events with start dates occurring any time 
after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the 
last day of study participation. At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until 
resolution or stabilization. 
 
 
 
8.3.5 Adverse Event Reporting 
 
All non-serious and unexpected adverse events will be kept in an adverse event log and 
reported annually.  Other adverse events that are both not serious and expected will not be 
reported. These are the expected adverse events listed in the protocol and consent as possible 
results from a study procedure. The investigator will meet all local reporting requirements as 
dictated by the UW IRB. 
 
 
8.3.6 Serious Adverse Event Reporting 
 
The PI will be immediately notified of any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
study intervention caused the event. Study endpoints that are serious adverse events must be 
reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the study intervention and the event (e.g., death from anaphylaxis). In that 
case, the investigator must immediately report the event.  
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable.  
The PI will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no 
case later than 7 calendar days after the PI's initial receipt of the information. In addition, the PI 
must notify FDA and all participating investigators in an Investigational New Drug (IND) safety 
report of potential serious risks, from clinical trials or any other source, as soon as possible, but 
in no case later than 15 calendar days after the PI determines that the information qualifies for 
reporting. 
 
 
8.3.7 Reporting Events to Participants 
 


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Participants will be informed about AEs and SAEs on an aggregate level as needed. 
 
 
8.3.8 Events of Special Interest 
 
 
Not applicable. 
 
 
8.3.9 Reporting of Pregnancy 
 
 
A positive pregnancy test will immediately be reported to the subject.  
 
8.4 Unanticipated Problems 
 
 
8.4.1 Definition of Unanticipated Problems (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria:  
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the Institutional 
Review Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied;  
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and  
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or 
recognized.  
 
 
8.4.2 Unanticipated Problem Reporting 
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional 
Review Board (IRB). The UP report will include the following information:  
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number;  
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP.  
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
• UPs that are serious adverse events (SAEs) will be reported to the IRB within 72 hours 
of the investigator becoming aware of the event.  
• Any other UP will be reported to the IRB 7 days of the investigator becoming aware of 
the problem.  
• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and the 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
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Office for Human Research Protections (OHRP) within 7 days of the IRB’s receipt of the report 
of the problem from the investigator. 
 
 
8.4.3 Reporting Unanticipated Problems to Participants 
 
 
Participants will be informed about UPs on an aggregate level as needed. 
 
9. Statistical Considerations 
 
9.1 Statistical Hypothesis 
 
Sildenafil: We expect sildenafil will improve RV energetic efficiency, systolic, and diastolic 
function. LV measures will be included in all subjects to ensure absence of worsening LV function 
(energy efficiency, systolic, and diastolic function) with RV afterload reduction. We expect that LV 
function will improve with sildenafil as well. 
Metoprolol: We expect metoprolol to improve cardiac filling times, resulting in an improved 
RV and LV energetic efficiency. 
  
9.2 Sample Size Determination 
 
 
As a pilot study, we propose enrolling and completing 10 subjects. Our prior study (n=9) 
demonstrates an RV energy efficiency of 1.09±0.26 mL/mJ, and thus we estimate that 10 
subjects will allow us to detect a 30% improvement in RV energy efficiency (alpha 0.05, beta 0.8) 
for either drug intervention. 
 
9.3 Populations for Analyses 
 
 
Participants who received at least one dose of the study intervention will be analyzed in 
a modified intention to treat analysis. Safety analysis will be completed in all subjects who 
received at least one dose of the study intervention.  
 
9.4 Statistical Analyses 
 
 
9.4.1 General Approach 
 
RV kinetic energy efficiency serves at the primary endpoint for both therapeutics. 
Secondary endpoints are LV kinetic energy efficiency and standard biventricular measures of RV 
and LV function (Table 1). All measures will be assessed by individuals blinded to the 
intervention, and results will be summarized as means +/- standard error. Data analysis will be 
quantitative, with differences among means compared using Wilcoxon Rank Sum tests for each 
therapeutic intervention. Comparisons between interventions will be with ANOVA. All p values 
will be two-sided, with p<0.05 used to define statistical significance. 
 
 
9.4.2 Analysis of the Primary Efficacy Endpoint 
 
To determine RV kinetic energy, a mask is applied to the time-resolved velocity images, 
and the kinetic energy across the cardiac cycle is computed using the formula: KEtotal=frame voxel∑1  
½ mv2, where m=mass and v=velocity. To characterize energy efficiency, the total KE across 
the cardiac cycle is normalized to the flow through the MPA (QP) and aorta (QS). Analysis will be 
completed in blinded fashion. RV energy efficiency measures will be compared using Wilcoxon 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
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Protocol version date: V1   8-30-2018 
 
24 
 
Rank Sum tests for each individual after each intervention. All p values will be two-sided, with 
p<0.05 used to define statistical significance. Comparison between intervention will be with 
ANOVA.  
 
 
9.4.3 Analysis of the Secondary Endpoint(s) 
 
LV kinetic energy efficiency will be determined similar to RV kinetic energy efficiency, 
and may not be dependent of the primary endpoint. Measures will be compared using Wilcoxon 
Rank Sum tests for each individual after each intervention. All p values will be two-sided, with 
p<0.05 used to define statistical significance. Comparison between interventions will be with 
ANOVA. Standard morphometric analysis (ventricular volumes, ejection fractions) will be 
compared similarly.  
 
 
9.4.4 Safety Analyses 
 
 
LV kinetic energy efficiency will be determined as a primary safety endpoint, and could 
worsen despite improvement in RV kinetic energy efficiency.  
 
 
9.4.5 Baseline Descriptive Statistics 
 
 
Baseline descriptive characteristics will not be compared, as each subject will serve as 
his/her pre-post comparison for each intervention.  
 
 
9.4.6 Planned Interim Analysis 
 
 
Not applicable. 
 
 
9.4.7 Sub-group Analysis 
 
 
Not applicable. 
 
 
9.4.8 Tabulation of Individual Participant Data  
 
 
Not applicable. 
 
10. Supporting Documentation and Operational Considerations 
 
10.1 Regulatory, Ethical and Study Oversight Considerations 
 
 
10.1.1 Informed Consent Process 
 
10.1.1.1 Consent/Assent and Other Informational Documents 
Provided to Participants 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks 
are given to the participant and written documentation of informed consent is required prior to 
starting intervention/administering study intervention. See consent materials. 
 
 
 
 
10.1.1.2 Consent Procedures and Documentation 
 


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Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. Consent 
forms will be Institutional Review Board (IRB)-approved and the participant will be asked to read 
and review the document. The investigator or delegate will explain the research study to the 
participant and answer any questions that may arise. A verbal explanation will be provided in 
terms suited to the participant’s comprehension of the purposes, procedures, and potential risks 
of the study and of their rights as research participants. Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participants 
should have the opportunity to discuss the study with their family or surrogates or think about it 
prior to agreeing to participate. The participant will sign the informed consent document prior to 
any procedures being done specifically for the study. Participants must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their 
records. The informed consent process will be conducted and documented in the source 
document (including the date), and the form signed, before the participant undergoes any study-
specific procedures. The rights and welfare of the participants will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
 
Prior to providing written informed consent, subjects will provide oral consent to fast and abstain 
from caffeine, alcohol, and consuming grapefruit prior to their study visits (part of the phone 
eligibility screen). Subjects will also provide oral permission to receive a copy of the consent 
form via email or post-mail. Subjects born premature that are not part of the NLP Cohort will 
provide oral consent for the release of their neonatal records, which will be used to confirm 
eligibility. If a Non-NLP subject incorrectly reports meeting the study inclusion/exclusion criteria 
(based on their neonatal records), they will be contacted by a member of the study team and 
any scheduled study visits will be cancelled. Additionally, their neonatal information/records will 
be destroyed.  
 
 
10.1.2 Study Discontinuation and Closure 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants and 
regulatory authorities. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), 
and PI will provide the reason(s) for the termination or suspension. Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.  
Circumstances that may warrant termination or suspension include, but are not limited 
to:  
• Determination of unexpected, significant, or unacceptable risk to participants  
• Demonstration of efficacy that would warrant stopping  
• Insufficient compliance to protocol requirements  
• Data that are not sufficiently complete and/or evaluable  
• Determination that the primary endpoint has been met  
• Determination of futility  
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the PI, IRB and/or Food and Drug Administration (FDA). 
 
 


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10.1.3 Confidentiality and Privacy 
 
 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators and their staff. This confidentiality is extended to cover testing of biological 
samples and future genetic tests (from biobanked samples) in addition to the clinical information 
relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study, or 
the data will be released to any unauthorized third party without prior written approval of the PI. 
All research activities will be conducted in as private a setting as possible.  
The study monitor, other authorized representatives of the PI, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records.  
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or PI 
requirements.  
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored on secure servers or in locked file cabinets. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived. 
 
 
 
10.1.4 Future Use of Stored Specimens and Data 
 
Data collected for this study will be analyzed and stored at the University of Wisconsin. 
After the study is completed, the de-identified, archived data may be be transmitted to and 
stored at the University of Wisconsin, for use by other researchers including those outside of the 
study. Permission to transmit data to future Data Repositories will be included in the informed 
consent.  
With the participant’s approval and as approved by local Institutional Review Boards 
(IRBs), de-identified biological samples will be stored in a biobank (in the PI’s lab) at the 
University of Wisconsin. These samples could be used to research the causes of prematurity 
associated cardiomyopathy, its complications and other conditions for which individuals with a 
history of premature birth are at increased risk, and to improve treatment. 
During informed consent, subjects will be informed that biobank storage of their blood 
and urine samples for future research is not optional.. However, subjects can choose if they 
want their samples to be used in future genetics research. Subjects can withdrawal consent by 
written request to the PI. 
When the study is completed, access to study data and/or samples will be provided through the 
NLP Repository.  
 
 
10.1.5 Key Roles and Study Governance 
 
Principal Investigator: 
Kara Goss, MD 
Assistant Professor of Medicine and Pediatrics 


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
PI: Kara Goss, MD 
Protocol version date: V1   8-30-2018 
 
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University of Wisconsin 
600 Highland Ave CSC H4/616 
Madison, WI 53792 
 
 
 
 
10.1.6 Safety Oversight 
 
.  
Safety oversight will be under the direction of the PI, who will conduct safety 
assessments annually at a minimum. The investigator will use her clinical expertise to evaluate 
the effect of the study procedures on the proposed primary and secondary outcomes, noting a 
direction of improvement, stagnation, or exacerbation. Any adverse and serious adverse events 
will be reviewed both cumulatively and individually to assess the continuing safety of the trial. 
The investigator will compare/contrast AEs/SAEs occurring after Sildenafil administration with 
those of Metoprolol. Findings from these assessments/evaluations will be used collectively to 
determine the continuing risk/benefit ratio of the study. Based on the risk/benefit ratio, the 
investigator may choose to continue the study under the current protocol specifications, 
continue the study with an altered design, or terminate the study.  
 
 
10.1.7 Clinical Monitoring - Not applicable: internal safety and data oversight 
 
10.1.8 Quality Assurance and Quality Control 
 
 
Annually at minimum, designated members of the study team will perform quality 
management of study conduct, data and biological specimen collection, documentation and 
completion. Quality control (QC) procedures will be implemented beginning with the data entry 
system, and data QC checks that will be run on the database will be generated. Any missing 
data or data anomalies will be communicated to PI for clarification/resolution.  
 
 
10.1.9 Data Handling and Record Keeping 
 
 
 
 
10.1.9.1 Data Collection and Management Responsibilities 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data. Hardcopies of the 
study visit worksheets will be provided for use as source document worksheets for recording 
data for each participant enrolled in the study. Data recorded in the electronic case report form 
(eCRF) derived from source documents should be consistent with the data recorded on the 
source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) and clinical laboratory data will be entered into RedCap, a 21 CFR Part 
11-compliant data capture system provided by the University of Wisconsin Department of 
Medicine. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
 
10.1.9.2 Study Records Retention 


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Study records will be retained for a minimum of three years after study completion 
(including the completion of data analyses) and funding expiration. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the PI, if applicable.  
 
10.1.10 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. Protocol deviations meeting the following 
criteria will be reported to the IRB within 7 days of the PI’s awareness of the event unless more 
immediate reporting is required: 
 
 
The deviation affected or had the potential to affect the subject’s rights, safety or 
welfare*; 
 
The deviation resulted in a change to the participant’s clinical or emotional condition or 
status; 
 
The deviation affected the integrity, accuracy and/or reliability of the research data; and 
 
The deviation resulted from willful or knowing misconduct on the part of the study team. 
 
*The IRB considers all study drug dosing errors (under- or over-dosing) to meet this 
criteria; therefore, all dosing errors require reporting to the IRB. 
 
10.1.11 Publication and Data Sharing Policy 
 
This study will be conducted in accordance with the following publication and data 
sharing policies and regulations:  
National Institutes of Health (NIH) Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination 
of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals. Data from this study may be 
requested from other researchers 2 years after the completion of the primary endpoint by 
contacting Kara Goss. 
 
10.1.12 Conflict of Interest Policy 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial.  


Title: Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study 
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10.2 Additional Considerations 
 
None.  
 
11. References 
 
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Cheitlin MD, Hutter AM, Jr., Brindis RG, et al. ACC/AHA expert consensus document. 
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Protocol version date: V1   8-30-2018 
 
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