Early and 1-year Hemodynamic Performance and Clinical Outcomes After Aortic Valve Replacement Using Two Pericardial Bioprostheses: A Multicenter Randomized Controlled Trial
Phase: NA
Conditions: Aortic Valve Disease
Sponsor: Seoul National University Hospital

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Prospective Randomized comparison Of prosthetic Valve Effective 
orifice area: One-year analysis of two bovine PERIcardial valves 
(PROVE-PERI trial) 
 
 
 
 
 
NCT 03796442 
 
Trial Protocol v 1.4 
 
Updated Dec 28, 2018 
 
 
 

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Protocol summary 
 
Trial name 
and number 
Prospective Randomized comparison Of prosthetic Valve Effective orifice 
area: One-year analysis of two bovine PERIcardial valves (PROVE-PERI trial) 
ClinicalTrial.gov 03796442 
Objectives 
This randomized controlled trial is designed to compare 1-year hemodynamic 
performances and clinical outcomes after aortic valve replacement (AVR) using 
a recently introduced and world-widely used bovine pericardial bioprostheses. 
Design 
Prospective randomized controlled trial 
Study periods 
IRB approval date ~ June 30, 2022 
Subjects 
Patients who are scheduled to undergo AVR 
Sample size 
Total 140 patients 
Methods 
Patients over 19 years of age who are scheduled to undergo AVR on a 
nonemergency basis and who are planned to undergo primary AVR using 
stented bioprostheses are assessed for eligibility for study enrollment. The 
exclusion criteria include (1) patients with concomitant mitral or tricuspid valve 
operation, (2) patients with infective endocarditis, (3) patients with severe left 
ventricular dysfunction (ejection fraction < 0.30), (4) patients with a medical 
history such as a malignant disease that might limit the possibility of mid-term 
follow-up and (5) patients who refuse study enrollment.  
Enrolled patients are randomly assigned to 1 of the 2 bioprostheses in a 1:1 
manner. After surgery, early clinical and hemodynamic outcomes are evaluated 
following the protocol. After discharge, all patients undergo regular 
postoperative follow-up and are evaluated with echocardiography at 1-year 
follow-up.  
Endpoints 
The primary endpoint of the PROVE-PERI trial was mean pressure gradient 
across the aortic valve (AVMPG) on 1-year echocardiographic follow-up. The 
secondary endpoints were the effective orifice area (EOA) on 1-year 
echocardiographic follow-up and 1-year clinical outcomes including all-cause 
mortality, cardiac death and major adverse event (MAEs). 
Safety 
Postoperative complications including operative mortality, low cardiac output, 
bleeding reoperation, perioperative myocardial infarction, perioperative stroke, 
acute kidney injury, respiratory complications, postoperative atrial fibrillation, 
and mediastinitis were monitored for safety.  
Expectations 
This trial will provide the objective hemodynamic and clinical data for 
individual prosthesis, and help the patients and surgeons to choose optimal 
prosthesis for aortic valve replacement (AVR).  

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Study Protocol 
1. Title 
Prospective Randomized comparison Of prosthetic Valve Effective orifice area: One-year analysis 
of two bovine PERIcardial valves (PROVE-PERI trial) 
 
2. Institutions 
Seoul National University Hospital (101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea) 
Seoul National University Bundang Hospital (82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-
si, Gyeonggi-do 13620, Korea) 
 
3. Principal investigator and co-investigators 
1) Principal investigators 
Ho Young Hwang (Department of Thoracic and Cardiovascular Surgery, Seoul National 
University Hospital) 
Cheong Lim (Department of Thoracic and Cardiovascular Surgery, Seoul National University 
Bundang Hospital) 
 
2) Co-investigators 
Yoonjin Kang (Department of Thoracic and Cardiovascular Surgery, Seoul National University 
Hospital) 
Ji Seong Kim (Department of Thoracic and Cardiovascular Surgery, Seoul National University 
Hospital) 
Jae Woong Choi (Department of Thoracic and Cardiovascular Surgery, Seoul National 
University Hospital) 
Jae Hang Lee (Department of Thoracic and Cardiovascular Surgery, Seoul National University 
Bundang Hospital) 
Jun Sung Kim (Department of Thoracic and Cardiovascular Surgery, Seoul National University 
Bundang Hospital) 
 
3) Sub-investigator 
Suk Ho Sohn (Department of Thoracic and Cardiovascular Surgery, Seoul National University 
Hospital) 
 

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4. Sponsor 
none 
 
5. Funding 
none 
 
6. Study period 
IRB approval – June 30, 2022 
 
7. Study subjects 
Patients who are scheduled to undergo AVR 
 
8. Background and Objectives 
1) Background 
Current guidelines demonstrate that aortic valve replacement ([AV]R) with a prosthetic valve is 
indicated for the patients with severe AV disease. [1] Many prosthetic valves have been 
introduced in the clinical practice, upgraded with their own characteristics, and contributed to 
the improved clinical outcomes after AVR. Among several types of prosthetic valves, 
bioprostheses have advantages in biocompatibility and in avoidance of long-term 
anticoagulation compared with mechanical valves, whereas they have disadvantages of limited 
durability and smaller effective orifice area (EOA). 
The AvalusTM (Medtronic, Minneapolis, MN) is one of most recently introduced stented bovine 
pericardial bioprostheses. [2] A prospective observational study, which is called PERIGON 
(PERIcardial SurGical AOrtic Valve ReplacemeNt) Pivotal Trial, have reported favorable 5-year 
hemodynamic performance and clinical outcomes after AVR using the AvalusTM valve.4 However, 
there has been no study that prospectively compared results after AVR using the AvalusTM with 
those after AVR using other bovine pericardial valves. 
To perform a comparative analysis for the efficacy and safety of this newly introduced 
bioprosthesis, a prospective randomized controlled trial (RCT) comparing the AvalusTM with the 
world-widely used Carpentier-Edwards PERIMOUNT Magna Ease (CEPME; Edwards Lifesciences, 
Irvine, CA) was designed by the authors. 
 
2) Hypothesis and Objectives 

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The present study is conducted to compare 1-year hemodynamic performances after AVR 
using the AvalusTM valve with those using the CEPME.  
We hypothesize that the AvalusTM was noninferior to the CEPME based on the mean pressure 
gradient across the aortic valve (AVMPG) at 1-year echocardiographic follow-up. 
 
9. Inclusion criteria, Exclusion criteria and Sample size calculation 
1) Inclusion criteria 
① Patients who are scheduled to undergo AVR 
② Over 19 years of age 
③ Patients who are planned to receive a bioprosthetic valve for aortic valve substitute 
④ Patients who or whose legal representative fill out a written consent form before 
the start of the clinical trial and patients who can comply with the clinical trial 
requirements 
2) Exclusion criteria 
① Patients with concomitant mitral or tricuspid valve operation 
② Patients with severe left ventricular dysfunction (ejection fraction < 0.30) 
③ Patients with infective endocarditis 
④ Patients with a medical history such as a malignant disease that might limit the 
possibility of mid-term follow-up  
⑤ Patients who refused study enrollment 
3) Sample size calculation 
The study is designed to have 80% power to detect 1-year AVMPG of 12.6±4.3mmHg for 
the study prosthesis [2] and 11.9±4.3mmHg for the control prosthesis, [3-5] with a 1-sided 
type I error of 2.5% and a noninferiority margin of 3mmHg. The noninferiority margin is 
determined by the values of 15mmHg for AVMPG of clinically significant aortic stenosis [6] 
and 12mmHg for AVMPG of the control prosthesis. Fifty-six patents in each group are needed 
to complete the study cohort. Allowing for a 20% dropout rate during the 1-year follow-up, 
we determine that the recruitment of 70 patients in each group is necessary. 
 
(1) Level of significance (α) = 0.025 
(2) Type II error (β) = 0.20, power of the test = 80% 
(3) Drop out rate = 20% 
(4) One-tailed test 

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H0(null hypothesis): 𝛍𝟏−𝛍𝟐≥ δ   
H1(alternative hypothesis): 𝛍𝟏−𝛍𝟐<  δ 
(μ1:  mean AVMPG of the study group on 1 −year echocardiographic follow −up ,  
 μ2:  mean AVMPG of the control group on 1 −year echocardiographic follow −up  
 δ: noninferiority margin) 
 
The calculation was performed using PASS Software(Power Analysis and sample size software: 
http://www.ncss.com), and the calculated formula is as follows. 
 
n = (Zα + Zβ)
2(σ1
2 + σ2
2)
((μ1 −μ2) −δ)
2
  
μ1 = mean AVMPG of the study group on 1 −year echocardiographic follow −up 
μ2 = mean AVMPG of the control group on 1 −year echocardiographic follow −up 
σ1 = standard deviation of AVMPG of the study group on 1 −year echocardiographic follow −up 
σ2 = standard deviation of AVMPG of the control group on 1 −year echocardiographic follow −up 
δ: noninferiority margin 
 
4) Subject recruitment plan 
Subject recruitment will be performed for the patients who are scheduled to undergo AVR and 
who are hospitalized at Seoul National University Hospital and Seoul National University Bundang 
Hospital after providing sufficient explanation and informed consents. The subjects will be 
recruited competitively.  
 
10. Methods 
1) Detailed process of the study 
Patients over 19 years of age who are scheduled to undergo AVR on a nonemergency basis 
and who are planned to undergo primary AVR using stented bioprostheses at 2 institutions 
are assessed for eligibility for study enrollment. After excluding the patients who meet the 
exclusion criteria and who refuse to participate, enrolled patients are randomly assigned to 1 
of the 2 bioprostheses in a 1:1 manner. 
Surgeries are performed under median sternotomy or upper partial sternotomy under 
cardiopulmonary bypass with cold cardioplegic arrest. After the diseased AV is excised, the 
annulus is prepared for landing the prosthesis, and the proper valve sizes for both types of 

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prostheses are decided before randomization. Then, randomization is performed with a web-
based block randomization method with randomly determined block sizes of 4 and 6. After 
randomization, the assigned prosthesis is implanted with non-everting transverse mattress 
sutures. The knot-tying is performed manually or by using an automated knot-fastener. 
Patients are evaluated with early clinical outcomes and early echocardiographic 
measurements. After discharge, all patients undergo regular postoperative follow-up through 
the outpatient clinic at 3- to 6-month intervals and are interviewed by telephone for 
confirmation of their condition if the last clinic visit has not been conducted as scheduled. At 
postoperative 1-year, clinical outcomes and echocardiographic measurements are evaluated 
as scheduled.  
 
※ Randomization : Patients who meet the inclusion criteria and the exclusion criteria are 
randomly assigned to 1 of the 2 bioprostheses in a 1:1 manner. Randomization is performed 
with a web-based block randomization method (https://mrcc.snuh.org/) with randomly 
determined block sizes of 4 and 6, considering the institution as a stratification factor.   
 
2) Outcome measures 
1) Demographics: age, sex, height, weight, BMI, BSA, diagnosis, operation name 
2) Preoperative data 
- Risk factors: DM, HTN, smoking, dyslipidemia, stroke, COPD, CKD, chronic liver disease, 
coronary disease, peripheral vascular disease, history of cardiac surgery, New York Heart 
Association functional class, STS mortality risk, EuroSCORE II 
- Echocardiographic measurements: Effective orifice area, mean pressure gradient, peak 
pressure gradient, LA dimension, LV ejection fraction, LV end diastolic dimension, LV end 
systolic dimension, pulmonary artery systolic pressure, TR severity, etc. 
- Electrocardiography 
- Laboratory tests: CBC, routine chemistry, NT-proBNP, CRP, ABGA, lactate, PT, aPTT 
- CT scan (thoracoabdominal CT angio) 
- Pulmonary function test 
3) Operative data: CPB time, ACC time, concomitant procedures, operative findings 
4) Postoperative data 
- Early clinical outcomes: op mortality, op morbidities (low cardiac output, bleeding 
reoperation, perioperative myocardial infarction, perioperative stroke, acute kidney injury, 
respiratory complications, postoperative atrial fibrillation, and mediastinitis) 

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- Echocardiographic measurements: Effective orifice area, mean pressure gradient, peak 
pressure gradient, LA dimension, LV ejection fraction, LV end diastolic dimension, LV end 
systolic dimension, pulmonary artery systolic pressure, TR severity, etc. 
- Electrocardiography: 1st, 2nd and 3rd AV block, bundle branch block 
5) 1-year follow-up data 
- Clinical outcomes: all-cause mortality, cardiac death and major adverse events (valve-
related 
mortality, 
structural 
valve 
deterioration, 
nonstructural 
dysfunction,  
thromboembolic and bleeding events, prosthetic valve endocarditis, AV reintervention or 
the need for a new permanent pacemaker or defibrillator within 14 days after the index 
operation), last follow-up date, New York Heart Association functional class 
- Echocardiographic measurements: Effective orifice area, mean pressure gradient, peak 
pressure gradient, LA dimension, LV ejection fraction, LV end diastolic dimension, LV end 
systolic dimension, pulmonary artery systolic pressure, TR severity, etc. 
- Electrocardiography: 1st, 2nd and 3rd AV block, bundle branch block 
 
※ Primary clinical endpoint 
mean pressure gradient across the aortic valve (AVMPG) on 1-year echocardiographic follow-
up 
※ Secondary clinical endpoint 
the effective orifice area (EOA) on 1-year echocardiographic follow-up  
operative mortality, operative morbidities 
1-year clinical outcomes (all-cause mortality, cardiac death and major adverse events) 
 
3) Differences from previous treatments and studies 
 When compared with previous treatments, the operative strategies and perioperative 
management are identical, but only the bioprostheses used in the treatments are different.  
When compared with previous studies, all studies previously performed were prospective single-
arm designs or retrospective studies. To the best of our knowledge, the present study is the first 
prospective randomized controlled trial comparing results of AVR using the AvalusTM valve with 
those using another bovine pericardial valve that has been used worldwide. 
 
4) Risks associated with the study 
* Predicted risks 
Because both prostheses have proved their efficacy and safety by prospective pivotal trials 

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and many related studies, the predicted risks associated with the present study will be 
comparable to routinely performed aortic valve replacement.  
If any adverse event or risk occurs, providing the standard management for them will be 
sufficient.  
 
5) Criteria for suspension and dropout 
Patients who decline to participate in the trial are suspended or drop-out 
 
6) Safety 
Safety outcomes will be a composite of death from any cause and individual major 
postoperative complications including low cardiac output, bleeding reoperation, 
perioperative myocardial infarction, perioperative stroke, acute kidney injury, respiratory 
complications, postoperative atrial fibrillation, and mediastinitis. 
All safety outcome measures will be assessed and recorded at designated time intervals by 
research personnel at each individual center. Data regarding every event will be reviewed 
and adjudicated centrally by the principal investigator and sub-investigator. 
 
7) Efficacy 
Efficacy analysis will be performed for ITT(Intention to treat) group, and supplemental 
analysis will be performed for PP(Per protocol) and As treated group. The primary endpoint 
will be concluded as ‘noninferior’ if both ITT and PP analyses confirm the noninferiority. 
ITT group includes all study population. PP group is constituted from the ITT group after 
excluding the patients with major violation of the study protocol.  
The null hypothesis was that the AvalusTM was inferior to the CEPME based on the AVMPG 
at 1-year echocardiographic follow-up, with a non-inferiority margin of 3mmHg. The result 
for the primary endpoint was presented with 97.5% one-sided confidence interval for mean 
difference between groups. The non-inferiority test was performed using a t-test which 
compared mean difference between groups with the non-inferiority margin under the one-
sided significance level of 0.025. 
For analysis of 1-year clinical outcomes including all-cause mortality, cardiac death, and 
MAEs, events were counted at postoperative 1 year, and comparisons between the 2 groups 
were made using the chi-square test and Fisher’s exact test. A P value of < .050 was 
considered statistically significant. 
 

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8) Schedules 
① Study planning : October 1, 2018 – November 31, 2018 
② Enrollment : January 1, 2019 (or after IRB approval) – June 30, 2022 
③ Data analysis and reporting : January 1, 2022 – December 31, 2022 
 
11. Data monitoring and Safety committee 
1) Monitoring committee 
Ho Young Hwang (Department of Thoracic and Cardiovascular Surgery, Seoul National 
University Hospital) 
Suk Ho Sohn (Department of Thoracic and Cardiovascular Surgery, Seoul National University 
Hospital) 
 
2) Data and Safety Monitoring List  
Operative mortality, low cardiac output, bleeding reoperation, perioperative myocardial 
infarction, perioperative stroke, acute kidney injury, respiratory complications, postoperative 
atrial fibrillation, and mediastinitis 
 
3) Data and Safety Monitoring Periods 
Safety outcomes will be monitored every 6 months. 
 
4) Reporting drug adverse events, non-compliance, or unpredicted events 
If any drug adverse event, non-compliance, or unpredicted event occurs, they must be 
reported within 15 working days from the date of recognition. 
 
5)  Withdrawal of the trial 
If critical adverse events or complications associated with the trial occur and it is impossible 
to keep the trial going on, the trial will be withdrawed. 
 
12. Ethics 
The Investigators and all parties involved will conduct this study in adherence to the ethical 
principles based on Declaration of Helsinki, GCP, ICH guidelines and the applicable national and 
local laws and regulatory requirements. Relevant study documentation will be submitted to Ethics 
Committees of participating centers, according to local/national requirements, for review. Written 

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approval of the study must be obtained locally before the study commences at each participating 
center. Once protocol amendments or consent form modifications are approved and implemented 
at the lead center, updated documents will be provided to participating centers. On completion 
of the study, the regulatory authorities will be notified that the study has ended.  
 
13. References 
[1] Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, et al. 2014 
AHA/ACC guideline for the management of patients with valvular heart disease: a report of the 
American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J 
Thorac Cardiovasc Surg. 2014;148:e1-e132. 
[2] Klautz RJM, Kappetein AP, Lange R, Dagenais F, Labrousse L, Bapat V, et al. Safety, effectiveness 
and haemodynamic performance of a new stented aortic valve bioprosthesis. Eur J Cardiothorac 
Surg. 2017;52:425-431. 
[3] Fiegl K, Deutsch MA, Rondak IC, Lange R, Guenzinger R. Matched Comparison of Two Different 
Biological Prostheses for Complete Supra-annular Aortic Valve Replacement. Thorac Cardiovasc 
Surg. 2015;63:459-66. 
[4] Wendt D, Thielmann M, Plicht B, Aßmann J, Price V, Neuhäuser M, et al. The new St Jude 
Trifecta versus Carpentier-Edwards Perimount Magna and Magna Ease aortic bioprosthesis: is 
there a hemodynamic superiority? J Thorac Cardiovasc Surg. 2014;147:1553-60. 
[5] Wyss TR, Bigler M, Stalder M, Englberger L, Aymard T, Kadner A, et al. Absence of prosthesis-
patient mismatch with the new generation of Edwards stented aortic bioprosthesis. Interact 
Cardiovasc Thorac Surg. 2010;10:884-7. 
[6] Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, et al. 
Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. 
Eur J Echocardiogr. 2009;10:1-25.